Benzoxepin PI3K inhibitor compounds and methods of use

ABSTRACT

Benzoxepin compounds of Formula I, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, wherein: Z 1  is CR 1  or N; Z 2  is CR 2  or N; Z 3  is CR 3  or N; Z 4  is CR 4  or N; and where (i) X 1  is N and X 2  is S, (ii) X 1  is S and X 2  is N, (iii) X 1  is CR 7  and X 2  is S, (iv) X 1  is S and X 2  is CR 7 ; (v) X 1  is NR 8  and X 2  is N, (vi) X 1  is N and X 2  is NR 8 , (vii) X 1  is CR 7  and X 2  is O, (viii) X 1  is O and X 2  is CR 7 , (ix) X 1  is CR 7  and X 2  is C(R 7 ) 2 , (x) X 1  is C(R 7 ) 2  and X 2  is CR 7 ; (xi) X 1  is N and X 2  is O, or (xii) X 1  is O and X 2  is N, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This non-provisional application filed under 37 CFR §1.53(b) is acontinuation of U.S. Ser. No. 14/162,520 filed on 23 Jan. 2014, which isa continuation of U.S. Ser. No. 13/568,707, now U.S. Pat. No. 8,673,952,filed on 7 Aug. 2012, which is a continuation of U.S. Ser. No.12/890,810, now U.S. Pat. No. 8,263,633, filed on 27 Sep. 2010, and alsoclaims the benefit under 35 USC §119(e) of U.S. Provisional ApplicationSer. No. 61/246,386 filed on 28 Sep. 2009, each of which is incorporatedby reference in its entirety.

FIELD OF THE INVENTION

The invention relates generally to compounds with anti-cancer activityand more specifically to compounds which inhibit PI3 kinase activity.The invention also relates to methods of using the compounds for invitro, in situ, and in vivo diagnosis or treatment of mammalian cells,or associated pathological conditions.

BACKGROUND OF THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of anumber of phospholipids found in cell membranes. In recent years it hasbecome clear that PI plays an important role in intracellular signaltransduction. Cell signaling via 3′-phosphorylated phosphoinositides hasbeen implicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity(Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsiblefor generating these phosphorylated signaling products,phosphatidylinositol 3-kinase (also referred to as PI 3-kinase or PI3K),was originally identified as an activity associated with viraloncoproteins and growth factor receptor tyrosine kinases thatphosphorylate phosphatidylinositol (PI) and its phosphorylatedderivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al(1992) Trends Cell Biol 2:358-60).

Phosphoinositide 3-kinases (PI3K) are lipid kinases that phosphorylatelipids at the 3-hydroxyl residue of an inositol ring (Whitman et al(1988) Nature, 332:664). The 3-phosphorylated phospholipids (PIP3s)generated by PI3-kinases act as second messengers recruiting kinaseswith lipid binding domains (including plekstrin homology (PH) regions),such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding ofAkt to membrane PIP3s causes the translocation of Akt to the plasmamembrane, bringing Akt into contact with PDK1, which is responsible foractivating Akt. The tumor-suppressor phosphatase, PTEN, dephosphorylatesPIP3 and therefore acts as a negative regulator of Akt activation. ThePI3-kinases Akt and PDK1 are important in the regulation of manycellular processes including cell cycle regulation, proliferation,survival, apoptosis and motility and are significant components of themolecular mechanisms of diseases such as cancer, diabetes and immuneinflammation (Vivanco et al (2002) Nature Rev. Cancer 2:489; Phillips etal (1998) Cancer 83:41).

The main PI3-kinase isoform in cancer is the Class I PI3-kinase, p110 α(alpha) (U.S. Pat. No. 5,824,492; U.S. Pat. No. 5,846,824; U.S. Pat. No.6,274,327). Other isoforms are implicated in cardiovascular andimmune-inflammatory disease (Workman P (2004) Biochem Soc Trans32:393-396; Patel et al (2004) Proceedings of the American Associationof Cancer Research (Abstract LB-247) 95th Annual Meeting, March 27-31,Orlando, Fla., USA; Ahmadi K and Waterfield Md. (2004) Encyclopedia ofBiological Chemistry (Lennarz W J, Lane M D eds) Elsevier/AcademicPress).

The PI3 kinase/Akt/PTEN pathway is an attractive target for cancer drugdevelopment since such agents would be expected to inhibitproliferation, reverse the repression of apoptosis and surmountresistance to cytotoxic agents in cancer cells. PI3 kinase inhibitorshave been reported (Folkes et al (2008) J. Med. Chem. 51:5522-5532;Yaguchi et al (2006) Jour. of the Nat. Cancer Inst. 98(8):545-556; U.S.Pat. No. 7,173,029; U.S. Pat. No. 7,037,915; U.S. Pat. No. 6,608,056;U.S. Pat. No. 6,608,053; U.S. Pat. No. 6,838,457; U.S. Pat. No.6,770,641; U.S. Pat. No. 6,653,320; U.S. Pat. No. 6,403,588; U.S. Pat.No. 6,703,414; WO 97/15658; WO 2006/046031; WO 2006/046035; WO2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US2004/092561; WO 2004/007491; WO 2004/006916; WO 2003/037886; US2003/149074; WO 2003/035618; WO 2003/034997; US 2003/158212; EP 1417976;US 2004/053946; JP 2001247477; JP 08175990; JP 08176070), including p110alpha binding activity (US 2008/0207611; US 2008/0039459; US2008/0076768; WO 2008/073785; WO 2008/070740).

SUMMARY OF THE INVENTION

The invention relates generally to benzoxepin compounds of Formula Iwith anti-cancer activity, and more specifically with PI3 kinaseinhibitory activity. Certain hyperproliferative disorders arecharacterized by the modulation of PI3 kinase function, e.g. bymutations or overexpression of the proteins. Accordingly, the compoundsof the invention may be useful in the treatment of hyperproliferativedisorders such as cancer. The compounds may inhibit tumor growth inmammals and may be useful for treating human cancer patients.

The invention also relates to methods of using the benzoxepin compoundsof Formula I for in vitro, in situ, and in vivo diagnosis or treatmentof mammalian cells, organisms, or associated pathological conditions.

Formula I compounds include:

and stereoisomers, geometric isomers, tautomers, or pharmaceuticallyacceptable salts thereof, wherein: Z¹ is CR¹ or N; Z² is CR² or N; Z³ isCR³ or N; Z⁴ is CR⁴ or N; and where (i) X¹ is N and X² is S, (ii) X¹ isS and X² is N, (iii) X¹ is CR⁷ and X² is S, (iv) X¹ is S and X² is CR⁷;(v) X¹ is NR⁸ and X² is N, (vi) X¹ is N and X² is NR⁸, (vii) X¹ is CR⁷and X² is O, (viii) X¹ is O and X² is CR⁷, (ix) X¹ is CR⁷ and X² isC(R⁷)₂, or (x) X¹ is C(R⁷)₂ and X² is CR⁷. The various substituents areas defined herein.

Another aspect of the invention provides a pharmaceutical compositioncomprising a benzoxepin compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutical composition may further compriseone or more additional therapeutic agent.

Another aspect of the invention provides methods of inhibiting PI3kinase activity, comprising contacting a PI3 kinase with an effectiveinhibitory amount of a compound of Formula I.

Another aspect of the invention provides methods of preventing ortreating a hyperproliferative disease or disorder modulated by PI3kinases, comprising administering to a mammal in need of such treatmentan effective amount of a compound of Formula I. Examples of suchhyperproliferative disease or disorder include, but are not limited to,cancer.

Another aspect of the invention provides methods of preventing ortreating a hyperproliferative disorder, comprising administering to amammal in need of such treatment an effective amount of a compound ofFormula I, alone or in combination with one or more additional compoundshaving anti-hyperproliferative properties.

In a further aspect the present invention provides a method of using acompound of this invention to treat a hyperproliferative disease orcondition modulated by PI3 kinase in a mammal.

An additional aspect of the invention is the use of a compound of thisinvention for treating cancer modulated by PI3 kinase in a mammal.

Another aspect of the invention includes kits comprising a compound ofFormula I, a container, and optionally a package insert or labelindicating a treatment.

Another aspect of the invention includes methods of preparing, methodsof separating, and methods of purifying compounds of Formula I.

Another aspect of the invention includes novel intermediates useful forpreparing Formula I compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a synthetic route to2-Bromo-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 5.

FIG. 2 shows a synthetic route to8-Amino-4,5-dihydro-6-oxa-1-thia-9-aza-benzo[e]azulene-2-carboxylic acid(2-chloro-phenyl)-amide 15 and amide intermediates 16.

FIG. 3 shows a synthetic route to8-Chloro-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1,9-diaza-benzo[e]azulene21.

FIG. 4 shows a synthetic route to8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 from8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25

FIG. 5 shows a synthetic route to8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene235, and sulfonamides 32, 445, 455.

FIG. 6 shows a synthetic route to 36 and 38 from8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene235

FIG. 7 shows a synthetic route to 39, 40, and 41 from8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene235

FIG. 8 shows a synthetic route to 47 from 24

FIG. 9 shows a synthetic route to 51 from 27

FIG. 10 shows a synthetic route to 56 from 53 and 27

FIG. 11 shows a synthetic route to 62 from 58 and 27

FIG. 12 shows a synthetic route to 66a and 66b from 63

FIG. 13 shows a synthetic route to 69, 70, and 71 from 64

FIG. 14 shows a synthetic route to 75

FIG. 15 shows a synthetic route to 76 and 77

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

DEFINITIONS

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms (C₁-C₁₂), wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. In anotherembodiment, an alkyl radical is one to eight carbon atoms (C₁-C₈), orone to six carbon atoms (C₁-C₆). Examples of alkyl groups include, butare not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu,i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkylene” as used herein refers to a saturated linear orbranched-chain divalent hydrocarbon radical of one to twelve carbonatoms (C₁-C₁₂), wherein the alkylene radical may be optionallysubstituted independently with one or more substituents described below.In another embodiment, an alkylene radical is one to eight carbon atoms(C₁-C₈), or one to six carbon atoms (C₁-C₆). Examples of alkylene groupsinclude, but are not limited to, methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at leastone site of unsaturation, i.e., a carbon-carbon, sp² double bond,wherein the alkenyl radical may be optionally substituted independentlywith one or more substituents described herein, and includes radicalshaving “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples include, but are not limited to, ethylenyl orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), and the like.

The term “alkenylene” refers to linear or branched-chain divalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at leastone site of unsaturation, i.e., a carbon-carbon, sp² double bond,wherein the alkenyl radical may be optionally substituted, and includesradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations. Examples include, but are not limited to,ethylenylene or vinylene (—CH═CH—), allyl (—CH₂CH═CH—), and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to eight carbon atoms (C₂-C₈) with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH), and the like.

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at leastone site of unsaturation, i.e., a carbon-carbon, sp triple bond, whereinthe alkynyl radical may be optionally. Examples include, but are notlimited to, ethynylene (—C≡C—), propynylene (propargylene, —CH₂C≡C—),and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms (C₃-C₁₂) as a monocyclicring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycleshaving 7 to 12 atoms can be arranged, e.g., as a bicyclo[4,5], [5,5],[5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ringatoms can be arranged as a bicyclo[5,6] or [6,6] system, or as bridgedsystems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of one hydrogen atom from a singlecarbon atom of a parent aromatic ring system. Some aryl groups arerepresented in the exemplary structures as “Ar”. Aryl includes bicyclicradicals comprising an aromatic ring fused to a saturated, partiallyunsaturated ring, or aromatic carbocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, biphenyl, indenyl,indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and thelike. Aryl groups are optionally substituted independently with one ormore substituents described herein.

“Arylene” means a divalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of two hydrogen atom from a twocarbon atoms of a parent aromatic ring system. Some arylene groups arerepresented in the exemplary structures as “Ar”. Arylene includesbicyclic radicals comprising an aromatic ring fused to a saturated,partially unsaturated ring, or aromatic carbocyclic ring. Typicalarylene groups include, but are not limited to, radicals derived frombenzene (phenylene), substituted benzenes, naphthalene, anthracene,biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene,1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups are optionallysubstituted

The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to about 20 ring atoms in which atleast one ring atom is a heteroatom selected from nitrogen, oxygen,phosphorus and sulfur, the remaining ring atoms being C, where one ormore ring atoms is optionally substituted independently with one or moresubstituents described below. A heterocycle may be a monocycle having 3to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selectedfrom N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), e.g.:a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles aredescribed in Paquette, Leo A.; “Principles of Modern HeterocyclicChemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series ofMonographs” (John Wiley & Sons, New York, 1950 to present), inparticular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960)82:5566. “Heterocyclyl” also includes radicals where heterocycleradicals are fused with a saturated, partially unsaturated ring, oraromatic carbocyclic or heterocyclic ring. Examples of heterocyclicrings include, but are not limited to, morpholin-4-yl, piperidin-1-yl,piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl,azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl,[1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro moieties are also includedwithin the scope of this definition. Examples of a heterocyclic groupwherein 2 ring carbon atoms are substituted with oxo (═O) moieties arepyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groupsherein are optionally substituted independently with one or moresubstituents described herein.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings, and includes fused ring systems (at least one ofwhich is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, e.g., 2-hydroxypyridinyl),imidazolyl, imidazopyridinyl, pyrimidinyl (including, e.g.,4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionallysubstituted independently with one or more substituents describedherein.

The heterocycle or heteroaryl groups may be carbon (carbon-linked), ornitrogen (nitrogen-linked) bonded where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder, such as the development or spread of cancer. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, e.g., byassessing the time to disease progression (TTP) and/or determining theresponse rate (RR).

The terms “cancer” refers to or describe the physiological condition inmammals that is typically characterized by unregulated cell growth. A“tumor” comprises one or more cancerous cells. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,and leukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinomaof the lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head andneck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Classes ofchemotherapeutic agents include, but are not limited to: alkyatingagents, antimetabolites, spindle poison plant alkaloids,cytoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies,photosensitizers, and kinase inhibitors. Chemotherapeutic agents includecompounds used in “targeted therapy” and conventional chemotherapy.Examples of chemotherapeutic agents include: erlotinib (TARCEVA®,Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU(fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®,Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin(cis-diamine,dichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CASNo. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology,Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide,CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine,NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCINO), Akti-1/2,HPPD, and rapamycin.

More examples of chemotherapeutic agents include: oxaliplatin(ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent(SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin(folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib(TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs),gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11,Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, II),vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chloranmbucil, AG1478,AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib(GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa andcyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gamma1I, calicheamicin omegaI1 (Angew Chem.Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, carminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche);ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, e.g., tamoxifen (including NOLVADEX®; tamoxifencitrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene,keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate);(ii) aromatase inhibitors that inhibit the enzyme aromatase, whichregulates estrogen production in the adrenal glands, such as, e.g.,4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate),AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR®(vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole;AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a1,3-dioxolane nucleoside cytosine analog); (iv) protein kinaseinhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid kinaseinhibitors; (vi) antisense oligonucleotides, particularly those whichinhibit expression of genes in signaling pathways implicated in aberrantcell proliferation, e.g., PKC-alpha, Raf and H-Ras, such as oblimersen(GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGF expressioninhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii)vaccines such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®,and VAXID®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitors such asLURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination with the PI3K inhibitors of theinvention include: alemtuzumab, apolizumab, aselizumab, atlizumab,bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumabmertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab,daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab,fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab,labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab,motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab,ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab,pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab,urtoxazumab, and visilizumab.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result e.g. from the oxidation, reduction, hydrolysis,amidation, deamidation, esterification, deesterification, enzymaticcleavage, and the like, of the administered compound. Accordingly, theinvention includes metabolites of compounds of the invention, includingcompounds produced by a process comprising contacting a compound of thisinvention with a mammal for a period of time sufficient to yield ametabolic product thereof.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.E.g., proton tautomers (also known as prototropic tautomers) includeinterconversions via migration of a proton, such as keto-enol andimine-enamine isomerizations. Valence tautomers include interconversionsby reorganization of some of the bonding electrons.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. A pharmaceuticallyacceptable salt may involve the inclusion of another molecule such as anacetate ion, a succinate ion or other counter ion. The counter ion maybe any organic or inorganic moiety that stabilizes the charge on theparent compound. Furthermore, a pharmaceutically acceptable salt mayhave more than one charged atom in its structure. Instances wheremultiple charged atoms are part of the pharmaceutically acceptable saltcan have multiple counter ions. Hence, a pharmaceutically acceptablesalt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, e.g., treatment of the free base with an inorganic acid, such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, trifluoroacetic acid, maleic acid, succinicacid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalicacid, glycolic acid, salicylic acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha hydroxy acid, such ascitric acid or tartaric acid, an amino acid, such as aspartic acid orglutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid,a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,e.g., treatment of the free acid with an inorganic or organic base, suchas an amine (primary, secondary or tertiary), an alkali metal hydroxideor alkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include, but are not limited to, organic salts derivedfrom amino acids, such as glycine and arginine, ammonia, primary,secondary, and tertiary amines, and cyclic amines, such as piperidine,morpholine and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminumand lithium.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine.

The terms “compound of this invention,” and “compounds of the presentinvention” and “compounds of Formula I” include compounds of Formulas Iand stereoisomers, geometric isomers, tautomers, solvates, metabolites,and pharmaceutically acceptable salts and prodrugs thereof

Benzoxepin Compounds

The present invention provides benzoxepin compounds, and pharmaceuticalformulations thereof, which are potentially useful in the treatment ofdiseases, conditions and/or disorders modulated by PI3 kinases. Morespecifically, the present invention provides compounds of Formula I:

and stereoisomers, geometric isomers, tautomers, or pharmaceuticallyacceptable salts thereof, wherein:

Z¹ is CR¹ or N;

Z² is CR² or N;

Z³ is CR³ or N;

Z⁴ is CR⁴ or N;

where (i) X¹ is N and X² is S, (ii) X¹ is S and X² is N, (iii) X¹ is CR⁷and X² is S, (iv) X¹ is S and X² is CR⁷; (v) X¹ is NR⁸ and X² is N, (vi)X¹ is N and X² is NR⁸, (vii) X¹ is CR⁷ and X² is O, (viii) X¹ is O andX² is CR⁷, (ix) X¹ is CR⁷ and X² is C(R⁷)₂, (x) X¹ is C(R⁷)₂ and X² isCR⁷; (xi) X¹ is N and X² is O, or (xii) X¹ is O and X² is N;

R¹ is selected from H, F, Cl, Br, I, —CN, —CF₃, —NO₂, and C₁-C₄ alkyl;

R², R³, R⁴, and R⁷ are independently selected from:

H, F, Cl, Br, I, —CN, —COR¹⁰, —CO₂R¹⁰, —C(═O)N(R¹⁰)OR¹¹,—C(═NR¹⁰)NR¹⁰R¹¹, —C(═O)NR¹⁰R¹¹, —NO₂, —NR¹⁰R¹¹, —NR¹²C(═O)R¹⁰,—NR¹²C(═O)OR¹¹, —NR¹²C(═O)NR¹⁰R¹¹, —NR¹²C(═O)(C₁-C₁₂ alkylene)NR¹⁰R¹¹,—NR¹²(C₁-C₁₂ alkylene)NR¹⁰R¹¹, —NR¹²(C₁-C₁₂ alkylene)OR¹⁰, —NR¹²(C₁-C₁₂alkylene)C(═O)NR¹⁰R¹¹, —OR¹⁰, —S(O)₂R¹⁰,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰R¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰C(═O)OR¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰C(═O)R¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)R¹⁰,

C₁-C₁₂ alkyl,

C₂-C₈ alkenyl,

C₂-C₈ alkynyl,

C₃-C₁₂ carbocyclyl,

C₂-C₂₀ heterocyclyl,

C₆-C₂₀ aryl,

C₁-C₂₀ heteroaryl,

—(C₃-C₁₂ carbocyclyl)-(C₁-C₁₂ alkyl),

—(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl),

—(C₆-C₂₀ aryl)-(C₁-C₁₂ alkyl),

—(C₁-C₂₀ heteroaryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₃-C₁₂ carbocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₃-C₁₂ carbocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-C(═O)—(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₆-C₂₀ aryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-C(═O)—(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)C(═O)OR¹⁰,

—(C₁-C₁₂ alkylene)-NR¹⁰R¹¹,

—(C₁-C₁₂ alkylene)NR¹²C(═O)R¹⁰,

—(C₁-C₁₂ alkylene)OR¹⁰,

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-NHC(═O)—(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-NR¹⁰R¹¹, and

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl)-NR¹⁰R¹¹,

where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, R¹⁰, —SR¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —NR¹⁰R¹¹, —NR¹²C(O)R¹⁰, —CO₂R¹⁰, —C(O)R¹⁰, —CONR¹⁰R¹¹,oxo, and —OR¹⁰;

A is selected from —C(═O)NR⁵R⁶, —NR⁵R⁶, C₆-C₂₀ aryl, C₂-C₂₀ heterocyclyland C₁-C₂₀ heteroaryl wherein aryl, heterocyclyl and heteroaryl areoptionally substituted with one or more groups independently selectedfrom F, Cl, Br, I, —CN, —COR¹⁰, —CO₂R¹⁰, —C(═O)N(R¹⁰)OR¹¹,—C(═NR¹⁰)NR¹⁰)R¹¹, —C(═O)NR¹⁰R¹¹, —NO₂, —NR¹⁰R¹¹, —NR¹²C(═O)R¹⁰,—NR¹²C(═O)OR¹¹, —NR¹²C(═O)NR¹⁰R¹¹, —NR¹²C(═O)(C₁-C₁₂ alkylene)NR¹⁰R¹¹,—NR¹²(C₁-C₁₂ alkylene)NR¹⁰R¹¹, —NR¹²(C₁-C₁₂ alkylene)OR¹⁰, —NR¹²(C₁-C₁₂alkylene)C(═O)NR¹⁰R¹¹, —OR¹⁰, —S(O)²R¹⁰,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰R¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰C(═O)OR¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰C(═O)R¹¹,

—C(═O)NR¹⁰(C₁-C₁₂ alkylene)R¹⁰,

C₁-C₁₂ alkyl,

C₂-C₈ alkenyl,

C₂-C₈ alkynyl,

C₃-C₁₂ carbocyclyl,

C₂-C₂₀ heterocyclyl,

C₆-C₂₀ aryl,

C₁-C₂₀ heteroaryl,

—(C₃-C₁₂ carbocyclyl)-(C₁-C₁₂ alkyl),

—(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl),

—(C₆-C₂₀ aryl)-(C₁-C₁₂ alkyl),

—(C₁-C₂₀ heteroaryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₃-C₁₂ carbocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₃-C₁₂ carbocyclyl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-C(═O)—(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₆-C₂₀ aryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl)-(C₁-C₁₂ alkyl),

—(C₁-C₁₂ alkylene)-C(═O)—(C₂-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)C(═O)OR¹⁰,

—(C₁-C₁₂ alkylene)-NR¹⁰R¹¹,

—(C₁-C₁₂ alkylene)NR¹²C(═O)R¹⁰,

—(C₁-C₁₂ alkylene)OR¹⁰,

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-(C₁-C₂₀ heterocyclyl),

—(C₁-C₁₂ alkylene)-NR¹⁰—(C₁-C₁₂ alkylene)-NHC(═O)—(C₁-C₂₀ heteroaryl),

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-NR¹⁰R¹¹, and

—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl)-(C₁-C₁₂ alkyl)-NR¹⁰R¹¹,

where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, R¹⁰, —SR¹⁰, —S(O)₂R¹⁰,—NR¹⁰R¹¹, —NR¹²C(O)R¹⁰, —CO₂R¹⁰, —C(O)R¹⁰, —CONR¹⁰R¹¹, and —OR¹⁰;

R⁵ is selected from H, and C₁-C₁₂ alkyl, optionally substituted with oneor more groups independently selected from F, Cl, Br, I, —CN, —CO₂H,—CONH₂, —CONHCH₃, —NH₂, —NO₂, —N(CH₃)₂, —NHCOCH₃, —NHS(O)₂CH₃, —OH,—OCH₃, —OCH₂CH₃, —S(O)₂NH₂, and —S(O)₂CH₃;

R⁶ is selected from C₁-C₁₂ alkyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₁-C₂₀ heteroaryl, and C₆-C₂₀ aryl, each optionallysubstituted with one or more groups independently selected from F, Cl,Br, I, —CH₃, —CH₂OH, —CH₂C₆H₅, —CN, —CF₃, —CO₂H, —C(O)CH₃, —NH₂, —NO₂,—N(CH₃)₂, —NHCOCH₃, —NHS(O)₂CH₃, —OH, oxo, —OCH₃, —OCH₂CH₃, —S(O)₂NH₂,—S(O)₂CH₃, —C(═O)NR¹⁰(C₁-C₁₂ alkylene)NR¹⁰R¹¹, phenyl, pyridinyl,tetrahydro-furan-2-yl, 2,3-dihydro-benzofuran-2-yl,1-isopropyl-pyrrolidin-3-ylmethyl, morpholin-4-yl, piperidin-1-yl,piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, —C≡CR¹³,—CH═CHR¹³, and —C(═O)NR¹⁰R¹¹;

or R⁵ and R⁶ together with the nitrogen atom to which they are attachedform C₂-C₂₀ heterocyclyl or C₁-C₂₀ heteroaryl optionally substitutedwith one or more groups selected from F, Cl, Br, I, CH₃, C(CH₃)₃,—CH₂OH, —CH₂CH₂OH, —CH₂C₆H₅, pyridin-2-yl, 6-methyl-pyridin-2-yl,pyridin-4-yl, pyridin-3-yl, pyrimidin-2-yl, pyrazin-2-yl,tetrahydro-furan-carbonyl, 2-methoxy-phenyl, benzoyl, cyclopropylmethyl,(tetra-furan-2-yl)methyl, 2,6-dimethyl-morpholin-4-yl,4-methyl-piperazine-carbonyl, pyrrolidine-1-carbonyl,cyclopropanecarbonyl, 2,4-difluoro-phenyl, pyridin-2-ylmethyl,morpholin-4-yl, —CN, —CF₃, —CO₂H, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —COCF₃,—COCH₃, —COCH(CH₃)₂, —NO₂, —NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —NHCOCH₃,—NCH₃COCH₃, —NHS(O)₂CH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂S(O)₂NHCH₃, —CH₂S(O)₂CH₂CH₃, —S(O)₂NHCH₃, —S(O)₂CH₂CH₃, —S(O)₂NH₂,—S(O)₂N(CH₃)₂ and —S(O)₂CH₃;

R⁸ is selected from H and C₁-C₄ alkyl;

R¹⁰, R¹¹ and R¹² are independently selected from H, C₁-C₁₂ alkyl,—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl), —(C₁-C₁₂ alkylene)-(C₆-C₂₀aryl), —(C₁-C₁₂ alkylene)-(C₃-C₁₂ carbocyclyl), C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl, each of which are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH₂C(CH₃)₂OH,—CH₂CH(CH₃)OH, —CH₂CO₂H, —CH₂CO₂CH₃, —CH₂NH₂, —(CH₂)₂N(CH₃)₂, —CH₂C₆H₅,—CN, —CF₃, —CO₂H, —C(O)CH₃, —C(O)CH(OH)CH₃, —CO₂CH₃, —CONH₂, —CONHCH₃,—CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NO₂, —N(CH₃)₂, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, —NHCOCH₃, —NHS(O)₂CH₃, ═O (oxo), —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OH, —OP(O)(OH)₂, —SCH₃, —S(O)₂CH₃, —S(O)₂NH₂,—S(O)₂N(CH₃)₂, —CH₂S(O)₂NHCH₃, —CH₂S(O)₂CH₂CH₃, —S(O)₂NHCH₃,—S(O)₂CH₂CH₃, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, cyclopropyl,cyclopentyl, oxetanyl, 4-methylpiperazin-1-yl, and 4-morpholinyl;

or R¹⁰ and R¹¹ together with the nitrogen atom to which they areattached form a C₂-C₂₀ heterocyclyl ring or C₁-C₂₀ heteroaryl each ofwhich are optionally substituted with one or more groups independentlyselected from F, Cl, Br, I, —CH₃, —CH₂OH, —CH₂C₆H₅, —CN, —CF₃, —CO₂H,—CONH₂, —CONHCH₃, —NO₂, —N(CH₃)₂, —NHCOCH₃, —NHS(O)₂CH₃, —OH, oxo,—OCH₃, —OCH₂CH₃, —S(O)₂NH₂, —S(O)₂CH₃, —CH(CH₃)₂, —CH₂CF₃, —CH₂CH₂OH and—C(CH₃)₂OH; and

R¹³ is selected from H, F, Cl, Br, I, —CH₃, —CH₂CH₃, —CN, —CF₃,—CH₂N(CH₃)₂, —CH₂OH, —CO₂H, —CONH₂, —CON(CH₃)₂, —NO₂, and —S(O)₂CH₃.

Exemplary embodiments include Formulas Ii and Iii

Exemplary embodiments include Formulas Iiii and Iiv

Exemplary embodiments include Formulas Iv and Ivi

Exemplary embodiments include Formulas Ivii and Iviii

Exemplary embodiments include Formulas Iix and Ix:

Exemplary embodiments include Formulas Ixi and Ixii:

Exemplary embodiments of Formula I compounds include wherein Z¹ is CR¹;Z² is CR²; Z³ is CR³; and Z⁴ is CR⁴.

Exemplary embodiments of Formula I compounds include wherein Z¹ is N; Z²is CR²; Z³ is CR³; and Z⁴ is CR⁴.

Exemplary embodiments of Formula I compounds include wherein Z¹ is CR¹;Z² is N; Z³ is CR³; and Z⁴ is CR⁴.

Exemplary embodiments of Formula I compounds include wherein Z¹ is CR¹;Z² is CR²; Z³ is N; and Z⁴ is CR⁴.

Exemplary embodiments of Formula I compounds include wherein Z¹ is CR¹;Z² is CR²; Z³ is CR³; and Z⁴ is N.

Exemplary embodiments include wherein A is —C(═O)NR⁵R⁶.

Exemplary embodiments include wherein R⁵ is CH₃.

Exemplary embodiments include wherein R⁶ is phenyl substituted with oneor more groups independently selected from F, Cl, Br, I, —CH₂OH,—CH₂C₆H₅, —CN, —CF₃, —CO₂H, —CONH₂, —CONHCH₃, —NO₂, —N(CH₃)₂, —NHCOCH₃,—NHS(O)₂CH₃, —OH, —OCH₃, —OCH₂CH₃, —S(O)₂NH₂, —S(O)₂CH₃, morpholin-4-yl,piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, —C≡CR¹³,and —CH═CHR¹³.

Exemplary embodiments include wherein R⁵ and R⁶ together with thenitrogen atom to which they are attached form morpholin-4-yl,piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl,azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl,[1,4]diazepan-1-yl, or indolinyl.

Exemplary embodiments include wherein A is C₂-C₂₀ heterocyclyl or C₁-C₂₀heteroaryl substituted with —CH₂OH, —CH₂CO₂H, —CH(CH₃)CH₂OCH₃, —CH₃,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂CF₃, —C(═O)CH₃, —C(═O)NHCH₃, —C(═O)N(CH₃)₂,—CO₂H, —CO₂CH₃, —CH₂CO₂CH₃, —NH₂, —NHC(═O)CH₃, —OH, —OCH₃, —S(O)₂CH₃,1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, 4-morpholinyl,(4-methylpiperazin-1yl)carboxamide, —CH₂(1H-1,2,4-triazol-5-yl),cyclopropyl, cyclopropylmethyl, or cyclobutyl.

Exemplary embodiments include wherein A is a C₁-C₂₀ heteroaryl selectedfrom pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl,1,3,4-oxadiazol-2(3H)-one, furanyl, thienyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,4-triazol-5(4H)-one,4,5-dihydro-1,2,4-triazin-6(1H)-one, tetrazolyl,pyrrolo[2,3-b]pyridinyl, indazolyl, 3,4-dihydroquinolinyl, andbenzo[d]thiazole.

Exemplary embodiments include wherein A is selected from the structures:

where R⁹ is independently selected from H, F, Cl, Br, I, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂CO₂H, —CH(CH₃)CH₂OCH₃, —CN, —CF₃,—CH₂CF₃, —CH₂NH₂, —CH₂CH₂NH₂, —C(═O)CH₃, —CH₂C(═O)NHCH₃, —C(═O)NHCH₃,—CO₂H, —CH₂CO₂CH₃, —NH₂, —OH, —OCH₃, —SCH₃, —S(O)₂CH₃,1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, 4-morpholinyl,morpholin-4-yl-ethyl, benzyl, and phenyl, where benzyl and phenyl areoptionally substituted with one or more groups selected from F, Cl, Br,I, —CH₂OH, —CH₂CO₂H, —CN, —CH₂NH₂, —CH₃, —C(═O)CH₃, —C(═O)NHCH₃, —CO₂H,—CH₂CO₂CH₃, —NH₂, —OCH₃, —S(O)₂CH₃, 1-methylpiperid-4-yl,4-methylpiperazin-1-yl, and 4-morpholinyl; and where the wavy lineindicates the site of attachment.

Exemplary embodiments include wherein A is selected from the structures:

where the wavy line indicates the site of attachment.

Biological Evaluation

Determination of the PI3 kinase activity of a Formula I compound ispossible by a number of direct and indirect detection methods. Certainexemplary compounds described herein were assayed for their p110α(alpha), and other isoform, PI3K binding activity (Example 601) and invitro activity against tumor cells (Example 602). Certain exemplarycompounds of the invention had PI3K binding activity IC₅₀ values lessthan 10 nM. Certain compounds of the invention had tumor cell-basedactivity IC₅₀ values less than 100 nM.

The cytotoxic or cytostatic activity of Formula I exemplary compoundswas measured by: establishing a proliferating mammalian tumor cell linein a cell culture medium, adding a Formula I compound, culturing thecells for a period from about 6 hours to about 5 days; and measuringcell viability (Example 602). Cell-based in vitro assays were used tomeasure viability, i.e. proliferation (IC₅₀), cytotoxicity (EC₅₀), andinduction of apoptosis (caspase activation).

The in vitro potency of Formula I exemplary compounds was measured bythe cell proliferation assay, CellTiter-Glo® Luminescent Cell ViabilityAssay, commercially available from Promega Corp., Madison, Wis. (Example602). This homogeneous assay method is based on the recombinantexpression of Coleoptera luciferase (U.S. Pat. No. 5,583,024; U.S. Pat.No. 5,674,713; U.S. Pat. No. 5,700,670) and determines the number ofviable cells in culture based on quantitation of the ATP present, anindicator of metabolically active cells (Crouch et al (1993) J. Immunol.Meth. 160:81-88; U.S. Pat. No. 6,602,677). The CellTiter-Glo® Assay wasconducted in 96 or 384 well format, making it amenable to automatedhigh-throughput screening (HTS) (Cree et al (1995) Anti Cancer Drugs6:398-404). The homogeneous assay procedure involves adding the singlereagent (CellTiter-Glo® Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium and multiplepipetting steps are not required. The system detects as few as 15cells/well in a 384-well format in 10 minutes after adding reagent andmixing.

The homogeneous “add-mix-measure” format results in cell lysis andgeneration of a luminescent signal proportional to the amount of ATPpresent. The amount of ATP is directly proportional to the number ofcells present in culture. The CellTiter-Glo® Assay generates a“glow-type” luminescent signal, produced by the luciferase reaction,which has a half-life generally greater than five hours, depending oncell type and medium used. Viable cells are reflected in relativeluminescence units (RLU). The substrate, Beetle Luciferin, isoxidatively decarboxylated by recombinant firefly luciferase withconcomitant conversion of ATP to AMP and generation of photons. Theextended half-life eliminates the need to use reagent injectors andprovides flexibility for continuous or batch mode processing of multipleplates. This cell proliferation assay can be used with various multiwellformats, e.g. 96 or 384 well format. Data can be recorded by luminometeror CCD camera imaging device. The luminescence output is presented asrelative light units (RLU), measured over time.

The anti-proliferative effects of Formula I exemplary compounds weremeasured by the CellTiter-Glo® Assay (Example 602) against several tumorcell lines. Potency EC₅₀ values were established for the testedcompounds. The range of in vitro cell potency activities was about 100nM to about 10 μM. Certain tested compounds had EC₅₀ values of less than1 micromolar (1 μM) in stopping proliferation of certain tumor celllines.

Certain ADME properties were measured for certain exemplary compounds byassays including: Caco-2 Permeability (Example 603), HepatocyteClearance (Example 604), Cytochrome P450 Inhibition (Example 605),Cytochrome P450 Induction (Example 606), Plasma Protein Binding (Example607), and hERG channel blockage (Example 608).

Certain exemplary compounds were tested for efficacy by a doseescalation studies by administration in tumor xenograft Taconic nudemouse models (Example 609). The breast cancer cell line MDA-MB-361.1mouse model was administered certain exemplary Formula I compounds alongwith Vehicle (MCT, negative control). The tumor growth delay wasmeasured when dosed orally daily for 21 days at 50 and 100 mg/kg. Bodyweight change over the course of treatment was measured as an indicatorof safety. Treatment of the MDA-MB-361.1 mouse model with certainexemplary Formula I compounds caused tumor growth stasis, inhibition, orregression when dosed orally daily for 21 days.

Exemplary Formula I compounds Nos. 101-512 in Table 1 and Nos. 513-548in Table 2, were made, characterized, and tested for inhibition of PI3Kalpha (IC₅₀ p110 alpha less than 1 micromolar, μM) and selectivityaccording to the methods of this invention, and have the followingstructures and corresponding names (ChemDraw Ultra, Version 9.0.1,CambridgeSoft Corp., Cambridge Mass.). E.g., compound 101 had an IC₅₀ of0.031 micromole; compound 102 had an IC₅₀ of 0.0051 micromole; compound103 had an IC₅₀ of 0.0018 micromole; compound 106 had an IC₅₀ of 0.0057micromole; compound 109 had an IC₅₀ of 0.0013 micromole; compound 127had an IC₅₀ of 0.00005 micromole; compound 147 had an IC₅₀ of 0.021micromole; compound 151 had an IC₅₀ of 0.00020 micromole; and compound153 had an IC₅₀ of 0.058 micromole.

TABLE 1 No. Structure Name 101

((R)-2-Hydroxymethyl-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]- methanone 102

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid isopropyl-methyl-amide 103

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide 104

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid (2- methoxy-ethyl)-amide 105

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol 106

1H-Pyrazole-4-carboxylic acid {2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-ylmethyl}-amide 107

2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxyl acid ((S)-2-hydroxy-propyl)-amide108

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid[2-(2- hydroxy-ethoxy)-ethyl]-amide 109

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-l-thia-10-aza-benzo[e]azulen-9-yl}-[2-(1,1-dioxo-1S-thiomorpholin-4-yl)-ethyl]- amine 110

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(4-methyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza- benzo[c]azulene 111

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carboxylic acid (2- hydroxy-ethyl)-amide 112

2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid (2-hydroxy-ethyl)-amide 113

2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid (2,2-difluoro-ethyl)-amide114

8-[1-(2-Morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa- 3-thia-1-aza-benzo[e]azulene115

9-[1-(2-Morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa- 3-thia-1-aza-benzo[e]azulene116

(2-Morpholin-4-yl-ethyl)-(5-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl}-pyridin-2-yl)-amine117

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(1- methyl-pyrrolidin-3-ylmethyl)-amine118

{2-[2-(2,4-DifIuoro-phenyI)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(1- methyl-piperidin-4-ylmethyl)-amine119

[2-(4-Isopropyl-4H-[1,2,4]triazol-3- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-(2,2,2- trifluoro-ethyl)-amine 120

[2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-(2-methoxy- ethyl)-amine 121

Dimethyl-[3-(5-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyridin-2-yloxy)- propyl]-amine 122

1-tert-Butyl-5-[8-(1H-pyrazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-1H-[1,2,4]triazol-3- ylamine 123

Cyclopentylmethyl-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-amine 124

1-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}- piperidin-4-ol 125

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-(1,1-dioxo-S-thiomorpholin-4-yl)-4,5-dihydro-6-oxa-1- thia-10-aza-benzo[e]azulene 126

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}- phenethyl-amine 127

2-(3-amino-1-(2,4-difluorophenyl)-1H- 1,2,4-triazol-5-yl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8- carboxamide 128

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(2-methyl-pyridin-3-yl)-4,5-dihydro-6- oxa-3-thia-1-aza-benzo[e]azulene129

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(2-methoxy-pyridin-3-yl)-4,5-dihydro-6- oxa-3-thia-1-aza-benzo[e]azulene130

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(4-methanesulfonyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia- 10-aza-benzo[e]azulene 131

2-{[2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-ylmethyl]-amino}-ethanol 132

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-l-thia-10-aza-benzo[e]azulen-9-yl}-(2- morpholin-4-yl-ethyl)-amine 133

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(4- methoxy-benzyl)-amine 134

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamine 135

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(6-methyl-pyridin-3-yl)-4,5-dihydro-6- oxa-3-thia-1-aza-benzo[e]azulene136

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carbonitrile 137

(S)-1-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carbonyl]-pyrrolidine-2-carbonitrile138

((S)-3-Methyl-morpholin-4-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 139

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(4-methyl-pyridin-3-yl)-4,5-dihydro-6- oxa-3-thia-1-aza-benzo[e]azulene140

2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid isoxazol-3-ylamide 141

((R)-3-Methyl-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 142

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-cyano-ethyl)-cyclopentyl-amide 143

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-((E)-2-methanesulfonyl-vinyl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 144

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 145

2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-1H-pyrazol-1-yl)ethanol 146

1-isopropyl-5-(8-(3- (methylsulfonyl)phenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2- yl)-1H-1,2,4-triazole 147

3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin- 8-yl)benzoic acid 148

8-(3-Methanesulfonyl-phenyl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 149

3-{2-[2-(2,2,2-Trifluoro-cthyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-benzoic acid 150

2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-ethanol 151

2-(3-amino-1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine- 8-carboxamide 152

(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-acetic acid 153

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-cyano-ethyl)-methyl-amide 154

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-methyl-amide 155

Azocan-1-yl-[8-(1H-pyrazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 156

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid((R)-2-hydroxy-2-phenyl-ethyl)- methyl-amide 157

Azetidin-1-yl-[8-(1H-pyrazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 158

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]- pyrrolidin-1-yl-methanone 159

(4-Methyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 160

[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 161

Piperidin-1-yl-[8-(1H-pyrazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 162

((R)-2-Hydroxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[c]azulen-2-yl]-methanone 163

((R)-3-Methyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 164

(3,3-Dimethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 165

((R)-3-Hydroxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 166

(4-Hydroxy-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 167

(4-Methyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-2-yl]-methanone 168

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4-pyridin-2-yl-piperazin-1-yl)-methanone 169

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidmethyl-(2-pyridin-2-yl-ethyl)-amide 170

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl-phenethyl-amide 171

((R)-2-Methyl-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 172

((R)-3-Hydroxy-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 173

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidcyclohexyl-(2-hydroxy-ethyl)-amide 174

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidmethyl-[(R)-1-(tetrahydro-furan-2- yl)methyl]-amide 175

(4-Dimethylamino-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 176

((R)-3-Hydroxy-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 177

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4-pyrimidin-2-yl-piperazin-1-yl)-methanone 178

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4- yl)-methanone 179

1-{4-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carbonyl]-piperazin-l-yl}-ethanone180

N-Methyl-N-{(R)-1-[8-(1H-pyrazol-4-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-pyrrolidin-3- yl}-acetamide 181

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid((R)-2,3-dihydroxy-propyl)-methyl- amide 182

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-methoxy-ethyl)-methyl-amide 183

(4-Hydroxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 184

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-[4-((R)-tetrahydro-furan-2-carbonyl)-piperazin-1- yl]-methanone 185

[4-(2-Methoxy-ethyl)-piperazin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 186

[4-(2-Methoxy-phenyl)-piperidin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 187

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid[(R)-1-(2,3-dihydro-benzofuran-2- yl)methyl]-methyl-amide 188

2-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- ethanol 189

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(2- pyrrolidin-1-yl-ethyl)-amine 190

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-(1-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1-thia- 10-aza-benzo[e]azulene 191

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(5-methyl-pyridin-3-yl)-4,5-dihydro-6- oxa-3-thia-1-aza-benzo[e]azulene192

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-benzenesulfonamide193

2-Methyl-1-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)- propan-2-ol 194

(4-Benzoyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 195

(4-Cyclopropylmethyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 196

4-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carbonyl]-piperazine-1-carboxylicacid dimethylamide 197

(R)-Octahydro-pyrido[1,2-a]pyrazin-2-yl-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]- methanone 198

[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]- methanone 199

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-{4-[(R)-1-(tetrahydro-furan-2-yl)methyl]- piperazin-1-yl}-methanone 200

(4-Methanesulfonyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 201

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-((R)-3-trifluoromethyl-piperidin-1-yl)-methanone 202

((R)-3-Diethylamino-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 203

(4,4-Difluoro-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 204

[4-((2R,6R)-2,6-Dimethyl-morpholin-4-yl)-piperidin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-2-yl]-methanone 205

[4-(4-Methyl-piperazinc-1-carbonyl)-piperidin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 206

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-[4-(pyrrolidine-1-carbonyl)-piperidin-1-yl]- methanone 207

(4-Cyclopropanecarbonyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]- methanone 208

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4- pyridin-4-yl-[1,4]diazepan-1-yl)-methanone 209

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide 210

((R)-3-Dimethylamino-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]- methanone 211

2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)- propionic acid 212

2-{[2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-ylmethyl]-amino}-acetamide 213

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-((R)-3-trifluoromethyl-pyrrolidin-1-yl)- methanone 214

[4-(2,4-Difluoro-phenyl)-piperidin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]- methanone 215

(4-Methoxy-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 216

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-((R)-2-pyridin-2-ylmethyl-pyrrolidin-1-yl)- methanone 217

4-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carbonyl]-piperazine-1-sulfonic aciddimethylamide 218

2-Methyl-1-{4-[8-(1H-pyrazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperazin-1- yl}-propan-1-one 219

((R)-3-Methoxy-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 220

1-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carbonyl]-piperidine-4-carbonitrile221

(3,3-Difluoro-azetidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 222

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid((S)-1-isopropyl-pyrrolidin-3- ylmethyl)-methyl-amide 223

((R)-3-Methoxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 224

(4-Methoxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl]-methanone 225

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidmethyl-(2-morpholin-4-yl-2-oxo- ethyl)-amide 226

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4-pyridin-3-yl-piperazin-1-yl)-methanone 227

[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4- pyridin-2-yl-[1,4]diazepan-1-yl)-methanone 228

((R)-3-Morpholin-4-yl-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]- methanone 229

2,2,2-Trifluoro-1-{4-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperazin-1- yl}-ethanone 230

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(4-methanesulfonyl-phenyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 231

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-[2-(4-methyl-piperazin-1-yl)-ethyl]-amine 232

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 233

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza- benzo[e]azulene 234

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(2-methoxy-phenyl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulene 235

8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulene 236

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-azetidine-1-carboxylic acid tert-butyl ester 237

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(5-methanesulfonyl-pyridin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 238

8-(1-Methanesulfonyl-1H-pyrazol-4-yl)- 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulene 239

9-(2-Isopropoxy-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 240

2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-acctamide 241

N,N-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)- acetamide 242

2-({2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-methyl- amino)-ethanol 243

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-(4-isopropyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia- 10-aza-benzo[e]azulene 244

4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-butan- 2-ol 245

4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-butan- 1-ol 246

(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-propyl)- dimethyl-amine 247

N-(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin- 2-yl)-acetamide 248

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-(6-morpholin-4-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia- 10-aza-benzo[e]azulene 249

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 250

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}- (tetrahydro-pyran-4-yl)-amine 251

9-Cyclopentyl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulene 252

(4-tert-Butyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 253

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid diethylamide 254

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid isobutyl-methyl-amide 255

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidmethyl-(3-methyl-butyl)-amide 256

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(1,1-dioxo-tetrahydro-thiophen-3-yl)- methyl-amide 257

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidmethyl-(1-methyl-pyrrolidin-3-yl)- amide 258

2-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-ethanol 259

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonyl-azetidin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 260

(3-Methylamino-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 261

[1,4]Diazepan-1-yl-[8-(1H-pyrazol-4-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 262

Piperazin-1-yl-[8-(1H-pyrazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 263

1-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carbonyl]-piperidine-3-carboxylicacid 264

(3-Methyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone 265

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(2-trifluoromethyl-pyridin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 266

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(4-methoxy-pyridin-3-yl)-4,5-dihydro-6- oxa-3-thia-1-aza-benzo[e]azulene267

8-(6-Morpholin-4-yl-pyridin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxyethyl)-isopropylamide 268

8-(1-Methyl-1H-pyrazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxy-ethyl)-isopropyl-amide 269

8-[1-(2-Morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxy-ethyl)-isopropyl-amide270

8-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene-2-carboxylic acid(2- hydroxy-ethyl)-isopropyl-amide 271

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(2-methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza- benzo[e]azulene 272

4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2- methyl-butan-2-ol 273

(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-(2-morpholin-4-yl-ethyl)-amine 274

(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-(2-methanesulfonyl-ethyl)-amine 275

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(2- methoxy-ethyl)-amine 276

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}- isopropyl-amine 277

9-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxy-ethyl)-isopropyl-amide 278

9-(2-Amino-4-methyl-pyrimidin-5-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxy-ethyl)-isopropyl-amide 279

9-(6-Amino-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide 280

9-(4-Methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide 281

9-(2-Amino-pyrimidin-5-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide 282

9-(6-Methylamino-pyridin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxy-ethyl)-isopropyl-amide 283

9-(2-Ethoxy-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa- 3-thia-1-aza-benzo[e]azulene284

[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-isoxazol-3- yl-amine 285

2-{[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-ylmethyl]-amino}-ethanol 286

1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-ethane-1,2-diol 287

2-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol- 1-yl}-ethanol 288

2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-isobutyramide 289

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidcyclopentyl-(2-hydroxy-ethyl)-amide 290

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(3-hydroxy-propyl)-isopropyl-amide 291

8-(3,5-Dimethyl-isoxazol-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxy-ethyl)-isopropyl-amide 292

1-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-ethanol 293

1-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- propan-2-ol 294

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-pyrrolidin-1-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia- 10-aza-benzo[e]azulene 295

5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin- 2-ol 296

N′-(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-N,N-dimethyl-ethane-1,2-diamine 297

2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid oxetan-3-ylamide 298

9-(2-Methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide 299

9-(2-Methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2- carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide 300

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid((S)-1-hydroxymethyl-3-methyl- butyl)-amide 301

9-(1-Benzenesulfonyl-1H-pyrazol-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 302

2-{4-[2-(2-Pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol- 1-yl}-ethanol 303

2-(4-{2-[2-(1-Methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-ethanol 304

2-(1-Isopropyl-1H-imidazol-2-yl)-9-(2-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa- 1-thia-10-aza-benzo[e]azulene305

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(6-methoxy-pyridin-3-yl)-4,5-dihydro-6- oxa-3-thia-1-aza-benzo[e]azulene306

9-(2-Fluoro-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa- 3-thia-1-aza-benzo[e]azulene307

4,5-Dihydro-6-oxa-1-thia- benzo[e]azulene-2,8-dicarboxylic acid 2-{[2-chloro-5-(4-methyl-piperazine-1- carbonyl)-phenyl]-methyl-amide} 8-methylamide 308

4,5-Dihydro-6-oxa-1-thia- benzo[e]azulene-2,8-dicarboxylic acid 2-{[2-chloro-5-(4-methyl-piperazine-1- carbonyl)-phenyl]-methyl-amide}8-[(2- methanesulfonyl-ethyl)-amide] 309

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-4,5-dihydro-6-oxa- 1-thia-10-aza-benzo[e]azulene310

9-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-2- [2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1- thia-10-aza-benzo[e]azulene311

1-(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone 312

1-((2R,6S)-4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2,6-dimethyl-piperazin-1-yl)-ethanone 313

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 314

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-((3R,5S)-4-ethyl-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 315

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-[(3R,5S)-4-(2-fluoro-ethyl)-3,5-dimethyl-piperazin-1-yl]-4,5-dihydro-6-oxa-1-thia-10-aza- benzo[e]azulene 316

1-((2R,6S)-4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2,6-dimethyl-piperazin-1-yl)-2,2,2-trifluoro- ethanone 317

2-{4-[2-(1-Isopropyl-1H-imidazol-2-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}- ethanol 318

(R)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-propan-1-one 319

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide 320

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 321

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(propane-2-sulfonyl)-azetidin-3-yl]- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 322

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanol 323

(S)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-propan-1-one 324

N-(2-Hydroxy-ethyl)-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl}-pyrazol-1-yl)-isobutyramide 325

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(6-morpholin-4-yl-pyridin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 326

8-[1-(1,1-Dioxo-tetrahydro-1S-thiophen-3-yl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 327

2-(2-Oxo-1,2-dihydro-pyridin-3-yl)-4,5- dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-8-carboxylic acid amide 328

[5-(9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-2-yl)-1-isopropyl- 1H-pyrazol-4-yl]-methanol 329

2,2,2-Trifluoro-1-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-ethanol 330

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1H-pyridin-2-one331

9-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxy-ethyl)-isopropyl-amide332

2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)- propan-1-ol 333

N2-(2-chloro-5-(piperazine-1- carbonyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8- dicarboxamide 334

N2-(2-chloro-5-(piperazine-1- carbonyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide 335

5-{2-[2-(2,4-Difluoro-phenyl)-2H-[,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin- 2-ylamine 336

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza- benzo[e]azulene 337

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-(6-methoxy-4-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa- 1-thia-10-aza-benzo[e]azulene338

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 339

(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin- 2-yl)-dimethyl-amine 340

2-(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin- 2-ylamino)-ethanol 341

(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin- 2-yl)-(2-methoxy-ethyl)-amine342

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-pyridin-3-yl-4,5-dihydro-6-oxa-3-thia-1- aza-benzo[e]azulene 343

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(5-methoxy-pyridin-3-yl)-4,5-dihydro-6- oxa-3-thia-1-aza-benzo[e]azulene344

2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-ethylamine 345

2-Hydroxy-1-(3-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidin-1-yl)-propan-1-one 346

2-{4-[2-(4-Isopropyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]- pyrazol-1-yl}-ethanol 347

2-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- propan-1-ol 348

1-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}- piperazin-1-yl)-ethanone 349

1-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}- [1,4]diazepan-1-yl)-ethanone 350

9-[1,4]Diazepan-1-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 351

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-[(3R,5S)-3,5-dimethyl-4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-4,5-dihydro-6-oxa-1-thia- 10-aza-benzo[e]azulene 352

4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}- piperazin-2-one 353

1-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- piperidin-1-yl)-ethanone 354

2-Methyl-1-{4-[2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]- pyrazol-1-yl}-propan-2-ol 355

2-Methyl-1-(4-{2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-oxa-3-thia-1-aza-benzo[e]azulen-8-yl} pyrazol-1-yl)-propan-2-ol 356

3-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-4,4- dimethyl-oxazolidin-2-one 357

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-piperidin-1-yl}- acetamide 358

(R)-2-Hydroxy-1-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-piperidin- 1-yl}-propan-1-one 359

(S)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin- 1-yl}-propan-1-one 360

N2-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8- dicarboxamide 361

N2-(2-chloro-5-((S)-2- hydroxypropylcarbamoyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-2,8-dicarboxamide 362

1-(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- azetidin-1-yl)-ethanone 363

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(1-methanesulfonyl-azetidin-3-yl)-amine 364

N-(1-Acetyl-azetidin-3-yl)-N-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza- benzo[e]azulen-9-yl)-acetamide 365

4,5-Dihydro-6-oxa-1-thia- benzo[e]azulene-2,8-dicarboxylic acid 2-{[2-chloro-5-((R)-2-hydroxy- propylcarbamoyl)-phenyl]-methyl-amide}8-methylamide 366

1-(4-{2-[5-Amino-2-(2,4-difluoro- phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl}-pyrazol-1-yl)-2-methyl-propan-2-ol 367

1-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2- methyl-propan-2-ol 368

1-{4-[2-(5-Amino-2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol- 1-yl}-2-methyl-propan-2-ol 369

9-[1-((R)-2-Hydroxy-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene-2-carboxylic acid(2- hydroxy-ethyl)-isopropyl-amide 370

5-(8-Azetidin-3-yl-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H- [1,2,4]triazole 371

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-azetidin-1-yl}-acetamide 372

9-[1-(2,4-Difluoro-benzyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 373

9-[1-(2-Chloro-benzyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 374

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-3-yl-4,5-dihydro-6-oxa-3-thia- 1-aza-benzo[e]azulene 375

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1- aza-benzo[e]azulene 376

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-azetidin-1-yl}-ethanol 377

1-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2- methyl-propan-2-ol 378

(S)-2-Hydroxy-1-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-piperidin- 1-yl}-propan-1-one 379 380

2-Methyl-1-(4-{2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}- pyrazol-1-yl)-propan-2-ol 381

(S)-1-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-propan-2-ol 382

8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidcyclohexyl-(2-dimethylamino-ethyl)- amide 383

N2-(2-chloro-5-((2- hydroxyethyl)(methyl)carbamoyl)phenyl)-N2,N8-dimethyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide 384

N2-(2-chloro-5-(3-hydroxyazetidine-1- carbonyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide 385

N2-(2-chloro-5-(2- hydroxyethylcarbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8- dicarboxamide 386

N2-(2-chloro-5-((2- hydroxyethyl)(methyl)carbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine- 2,8-dicarboxamide 387

N2-(2-chloro-5-((R)-2- hydroxypropylcarbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8- dicarboxamide 388

(S)-1-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}- piperazin-1-yl)-2-hydroxy-propan-1-one389

(S)-1-(3-(2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidin-1-yl)-2-hydroxy-propan-1-one 390

9-[(3R,5S)-4-(2,2-Difluoro-ethyl)-3,5-dimethyl-piperazin-1-yl]-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza- benzo[e]azulene 391

1-((2R,6S)-4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2,6-dimethyl-piperazin-1-yl)-2,2-difluoro- ethanone 392

N-(2-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- ethyl)-acetamide 393

1,1-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)- ethylamine 394

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-azetidine-1-sulfonyl}-ethanol 395

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonyl-piperidin-4-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 396

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonyl-pyrrolidin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 397

2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-ethanone 398

(R)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin- 1-yl}-propan-1-one 399

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(6-pyrrolidin-1-yl-pyridin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 400

1-Isopropyl-5-(8-[1-(3-methyl-oxetan-3-ylmethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}- 1H-[1,2,4]triazol-3-ylamine 401

8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2- hydroxy-ethyl)-isopropyl-amide402

9-(2-Fluoro-5-methyl-pyridin-3-yl)-2-(2isopropyl-2H-[1,2,4]triazol-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 403

2-{4-[2-(5-Amino-2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol- 1-yl}-ethanol 404

1-(4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol- 1-yl}-3-methoxy-propan-2-ol 405

2-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol- 1-yl)-N-methyl-acetamide 406

8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 407

2-(5-Amino-2-isopropyl-2H- [1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid(1-methyl-azetidin-3-yl)-amide 408

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methyl-1H-imidazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 409

8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-(tetrahydro-pyran-4-yl)- amide 410

8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1-acetyl-piperidin-4-yl)-(2-hydroxy-ethyl)- amide 411

1-(4-[2-(1-azetidin-3-yl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2- methyl-propan-2-ol 412

2-methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)- propylamine 413

2-hydroxy-1-[3-(2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)- azetidin-1-yl]-propan-1-one 414

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethylamine 415

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-5-methyl-1H-pyridin-2-one 416

1-[3-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidin-1-yl]-ethanone 417

2-Methyl-1-{4-[2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]- pyrazol-1-yl}-propan-2-ol 418

{5-[2-(2-Isopropyl-2H-[1,2,4]triazol-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-1-methyl-1H-imidazol-2-yl}-methanol 419

5-(8-azetidin-3-yl-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-(2,4-difluoro- phenyl)-1H-[1,2,4]triazole420

2-Methyl-1-{4-[2-(1-oxetan-3-yl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}- propan-2-ol 421

1-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2- methyl-propan-2-ol 422

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2,2,2-trifluoro-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 423

8-(1-Isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 424

(S)-3-{3-[2-(2-Isopropyl-2H- [1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-propane-1,2-diol 425

(1-Amino-cyclopropyl)-{3-[2-(2- isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidin-1-yl}-methanone 426

4-(8-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-2-yl}-5-isopropyl-2-methyl-2,4-dihydro-[1,2,4]triazol-3-one 427

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2- methyl-propan-1-ol 428

2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamino}-2- methyl-propan-1-ol 429

1-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-5,5- dimethyl-imidazolidin-2-one 430

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonylmethyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 431

N2-(2-chloro-5-(2- hydroxyethylcarbamoyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3- d]oxepine-2,8-dicarboxamide 432

N2-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N2-methyl-N8-(2- (methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8- dicarboxamide 433

{2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-thia-10-aza-benzo[e]azulen-9-yl}-(1- methyl-azetidin-3-yl)-amine 434

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-oxetan- 3-yl-amine 435

Azetidin-3-yl-{2-[2-(2,4-difluoro- phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza- benzo[e]azulen-9-yl}-amine 436

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-5-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia- 10-aza-benzo[e]azulene 437

2-[2-(2,4-Difluoro-phenyl)-2H- [1,2,4]triazol-3-yl]-9-[5-methyl-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,5- dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 438

N2-(2-chloro-5-((S)-2- hydroxypropylcarbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-2,8- dicarboxamide 439

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-pyrazol-1-yl}-isobutyramide 440

2-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-imidazol- 1-yl}-ethanol 441

2-{5-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-imidazol- 1-yl}-ethanol 442

1-(4-{2-[2-(2-Hydroxy-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-2-methyl-propan-2-ol 443

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanesulfonic acid dimethylamide 444

2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-2-methyl-propan-1-one445

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidine-1-sulfonyl}-ethanol 446

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidin-1-yl}-isobutyramide 447

5-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl}-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-one 448

N2-(2-chloro-5-(3,3-difluoroazetidine-1- carbonyl)phenyl)-N2,N8-dimethyl-4,5- dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide 449

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- acetic acid 450

3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- propane-1,2-diol 451

2-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- N,N-dimethyl-acetamide 452

2-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}- acetamide 453

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-N-(1-methyl-azetidin-3-yl)-isobutyramide 454

8-{1-[2-(3,3-Difluoro-azetidine-1- sulfonyl)-ethyl]-azetidin-3-yl}-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 455

(2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidine-1-sulfonyl}-ethyl)-dimethyl-amine 456

4-Isopropyl-5-(8-[1-(3-methyl-oxetan-3-ylmethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-2,4-dihydro-[1,2,4]triazol-3-one 457

1-[3-(5-Chloro-2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)- azetidin-1-yl]-ethanone 458

2-(3-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol- 1-yl}-azetidin-1-yl)-ethanol459

1-(4-{2-[2-(2-Hydroxy-propyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-2-methyl-propan-2-ol 460

2-Methyl-1-(4-(2-[2-(2-morpholin-4 ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl}-pyrazol-1-yl)-propan-2-ol 461

Oxetan-3-yl-[2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)- ethyl]-amine 462

1-[4-(2-{2-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-2H-[1,2,4]triazol-3-yl}- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl)-pyrazol-1-yl]-2- methyl-propan-2-ol 463

1-Isopropyl-5-{8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H- [1,2,4]triazol-3-ylamine 464

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-N- methyl-isobutyramide 465

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanesulfonic acid Diethylamide 466

2-(5-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl}-[1,2,4]triazol-1-yl)-propan-1-ol 467

2-(4-{2-[2-(2-Morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol- 1-yl)-ethanol 468

1-(4-(2-(3-amino-1-isopropyl-1H-1,2,4- triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 469

2-Amino-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-2-methyl-propan-1-one470

N-Isopropyl-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-acetamide 471

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1- morpholin-4-yl-ethanone 472

N-(2-Hydroxy-2-methyl-propyl)-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}- acetamide 473

4-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one 474

4-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulen-2-yl}-2-isopropyl-5-methyl-2,4-dihydro- [1,2,4]triazol-3-one 475

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}- acetamide 476

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 477

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1-(2-methoxy-ethyl)-1H-pyridin-2-one 478

2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-[2-(2-methoxy-ethoxy)-pyridin-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 479

3-(8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1,4,4-trimethyl- imidazolidin-2-one 480

1-(3-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidin-1-yl)-2-methyl-propan-2-ol 481

2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-oxazol-2-ylmethyl-azetidin-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 482

phosphoric acid mono-(2-{4-[2-(2- isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethyl)ester 483

2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}- isobutyramide 484

diethyl-[2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}- pyrazol-1-yl)-ethyl]-amine 485

1-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-5,5- dimethyl-imidazolidine-2,4-dione486

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-imidazol-1-yl}-ethanol 487

8-(2-Fluoro-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa- 3-thia-1-aza-benzo[e]azulene488

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-1H-pyridin-2-one489

1-Isopropyl-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H- pyridin-2-one 490

(S)-2-Hydroxy-1-{3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}- propan-1-one 491

2-(2-Isopropyl-5-methyl-2H- [1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 492

1-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-3,5,5- trimethyl-imidazolidine-2,4-dione493

1-(4,5-Dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-2-yl)-5,5-dimethyl-imidazolidine-2,4-dione 494

(S)-3-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-propane-1,2-diol 495

9-(6-Fluoro-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa- 3-thia-1-aza-benzo[e]azulene496

5-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-y1]-1H-pyridin-2-one497

3-(2-Amino-ethyl)-1-(4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-5,5- dimethyl-imidazolidine-2,4-dione498

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1-(2-morpholin-4-yl-ethyl)-1H-pyridin-2-one 499

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}- ethanesulfonic acid dimethylamide500

8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid dimethylamide 501

{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-2-oxo-2H-pyridin-1- yl}-acetic acid 502

3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1-methyl-1H-pyridin-2-one 503

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-2-oxo-2H-pyridin-1- yl}-N,N-dimethyl-acetamide 504

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-2-oxo-2H-pyridin-1- yl}-acetamide 505

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1H-pyridin-2-one506

5-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1H-pyrimidine-2,4-dione 507

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-2-oxo-2H-pyridin-1- yl}-N-methyl-acetamide 508

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-N- methyl-acetamide 509

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}- N,N-dimethyl-acetamide 510

N-tert-Butyl-2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulcn-8-yl]-piperidin- 1-yl}-acetamide 511

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methoxy-ethyl)-piperidin-4-yl]-4,5- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 512

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}- ethanol

TABLE 2 No. Structure Name 513

2-(2-Isopropyl-2H-5-amino[1,2,4]triazol-3-yl)-8-fluoro-4,5-dihydro-6-oxa-3-thia- 1-aza-benzo[e]azulene 514

1-(8-Piperidin-4-yl-4,5- dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione 515

5-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1H-N-methylpyridin-2-one 516

2-(2-Isopropyl-2H-5-amino[1,2,4]triazol-3-yl)-9-fluoro-4,5-dihydro-6-oxa-3-thia- 1-aza-benzo[e]azulene 517

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-piperidin-4-olhydrochloride 518

2-(2-Isopropyl-5-methyl-2H- [1,2,4]triazol-3-yl)-8-[1-(2-methoxy-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3- thia-1-aza-benzo[e]azulene519

2-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-ethanol 520

1-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-3-methoxy-propan-2-ol521

8-[1-(2-Fluoro-ethyl)-azetidin-3-yl]-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 522

2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-phenyl}-acetamide 523

2-{4-Fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin- 1-yl}-N,N-dimethyl-acetamide524

{1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methyl}- urea 525

1-ethyl-3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]- urea 526

3-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin- 1-yl}-propan-1-ol 527

N-Isopropyl-2-{3-[2-(2-isopropyl-5- methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide 528

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1H-N-methylpyridin-2-one 529

2-(2-Isopropyl-5-methyl-2H- [1,2,4]triazol-3-yl)-8-oxetan-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 530

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-1H-pyridin-2-one531

2-(2-Isopropyl-2H-5- methoxymethyl[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 532

C-[2-(2-Isopropyl-5-methyl-2H- [1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]- methylamine 533

N-[2-(2-isopropyl-5-methyl-2H- [1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]- methanesulfonamide 534

2-(2-Isopropyl-2H-5- hydroxymethyl[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 535

2-(2-Isopropyl-5-methyl-2H- [1,2,4]triazol-3-yl)-8-piperidin-3S-yl-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 536

2-(2-Isopropyl-5-methyl-2H- [1,2,4]triazol-3-yl)-8-piperidin-3R-yl-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulene 537

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-2-yl-4,5-dihydro-6-oxa-3-thia- 1-aza-benzo[e]azulene 538

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1H-N-2-methoxyethylpyridin-2-one 539

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-1H-N-isopropylpyridin-2-one 540

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-9-yl]-(2-isopropoxy)pyridine 541

5-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-1H-pyridin-2-one542

{1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethyl}- urea 543

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-1-ethyl-pyridin-2-one 544

5-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen-8-yl]-1-(2-methoxyethyl)-pyridin-2-one 545

2-[2-(2-Isopropyl-5-methyl-2H- [1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]- benzenesulfonamide 546

(S)-1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-pyrrolidine- 2-carboxylic acid amide 547

(R)-2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-amino-1-oxopropan-2-yloxy)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 548

(S)-2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-amino-1-oxopropan-2-yloxy)- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Administration of Formula I Compounds

The Formula I compounds of the invention may be administered by anyroute appropriate to the condition to be treated. Suitable routesinclude oral, parenteral (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),vaginal, intraperitoneal, intrapulmonary and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the preferred route may vary with e.g. the conditionof the recipient. Where the compound is administered orally, it may beformulated as a pill, capsule, tablet, etc. with a pharmaceuticallyacceptable carrier or excipient. Where the compound is administeredparenterally, it may be formulated with a pharmaceutically acceptableparenteral vehicle and in a unit dosage injectable form, as detailedbelow.

A dose to treat human patients may range from about 10 mg to about 1000mg of Formula I compound. A typical dose may be about 100 mg to about300 mg of the compound. A dose may be administered once a day (QID),twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Methods of Treatment with Formula I Compounds

Compounds of the present invention are useful for treatinghyperproliferative diseases, conditions and/or disorders including, butnot limited to, those characterized by over expression of lipid kinases,e.g. PI3 kinase. Accordingly, another aspect of this invention includesmethods of treating or preventing diseases or conditions that can betreated or prevented by inhibiting lipid kinases, including PI3. In oneembodiment, the method comprises administering to a mammal in needthereof a therapeutically effective amount of a compound of Formula I,or a stereoisomer, geometric isomer, tautomer, or pharmaceuticallyacceptable salt thereof. In one embodiment, a human patient is treatedwith a compound of Formula I and a pharmaceutically acceptable carrier,adjuvant, or vehicle, wherein said compound of Formula I is present inan amount to detectably inhibit PI3 kinase activity.

Cancers which can be treated according to the methods of this inventioninclude, but are not limited to, breast, ovary, cervix, prostate,testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC),small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma,pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's and leukemia.

Another aspect of this invention provides a compound of this inventionfor use in the treatment of the diseases or conditions described hereinin a mammal, e.g., a human, suffering from such disease or condition.Also provided is the use of a compound of this invention in thepreparation of a medicament for the treatment of the diseases andconditions described herein in a warm-blooded animal, such as a mammal,e.g. a human, suffering from such disorder.

Pharmaceutical Formulations

In order to use a Formula I compound for the therapeutic treatment(including prophylactic treatment) of mammals including humans, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition. According to this aspect of theinvention there is provided a pharmaceutical composition comprising acompound of this invention in association with a pharmaceuticallyacceptable diluent or carrier.

A typical formulation is prepared by mixing a Formula I compound and acarrier, diluent or excipient. Suitable carriers, diluents andexcipients are well known to those skilled in the art and includematerials such as carbohydrates, waxes, water soluble and/or swellablepolymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents,water and the like. The particular carrier, diluent or excipient usedwill depend upon the means and purpose for which the compound of thepresent invention is being applied. Solvents are generally selectedbased on solvents recognized by persons skilled in the art as safe(GRAS) to be administered to a mammal. In general, safe solvents arenon-toxic aqueous solvents such as water and other non-toxic solventsthat are soluble or miscible in water. Suitable aqueous solvents includewater, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400,PEG 300), etc. and mixtures thereof. The formulations may also includeone or more buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents and other known additivesto provide an elegant presentation of the drug (i.e., a compound of thepresent invention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. E.g., the bulk drug substance (i.e., compound of thepresent invention or stabilized form of the Formula I compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent) is dissolved in a suitable solvent in the presence of one or moreof the excipients described above. The compound of the present inventionis typically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to enable patient compliancewith the prescribed regimen.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. E.g., acompound of Formula I having the desired degree of purity may optionallybe mixed with pharmaceutically acceptable diluents, carriers, excipientsor stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition,Osol, A. Ed.), in the form of a lyophilized formulation, milled powder,or an aqueous solution. Formulation may be conducted by mixing atambient temperature at the appropriate pH, and at the desired degree ofpurity, with physiologically acceptable carriers, i.e., carriers thatare non-toxic to recipients at the dosages and concentrations employed.The pH of the formulation depends mainly on the particular use and theconcentration of compound, but may range from about 3 to about 8.Formulation in an acetate buffer at pH 5 is a suitable embodiment.

The compound of this invention for use herein is preferably sterile. Inparticular, formulations to be used for in vivo administration must besterile. Such sterilization is readily accomplished by filtrationthrough sterile filtration membranes.

The compound ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

The pharmaceutical compositions of the invention comprising a Formula Icompound will be formulated, dosed and administered in a fashion, i.e.,amounts, concentrations, schedules, course, vehicles and route ofadministration, consistent with good medical practice. Factors forconsideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. The“therapeutically effective amount” of the compound to be administeredwill be governed by such considerations, and is the minimum amountnecessary to prevent, ameliorate, or treat the coagulation factormediated disorder. Such amount is preferably below the amount that istoxic to the host or renders the host significantly more susceptible tobleeding.

As a general proposition, the initial pharmaceutically effective amountof the inhibitor administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient bodyweight per day, with the typical initial range of compound used being0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, e.g., by coacervation techniques or by interfacialpolymerization, e.g., hydroxymethylcellulose or gelatin-microcapsulesand poly-(methylmethacylate) microcapsules, respectively, in colloidaldrug delivery systems (e.g., liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington's Pharmaceutical Sciences16th edition, Osol, A. Ed. (1980).

Sustained-release preparations of Formula I compounds may be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (e.g.,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of Formula I suitable for oral administrationmay be prepared as discrete units such as pills, capsules, cachets ortablets each containing a predetermined amount of a compound of FormulaI.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof compounds of Formula I intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, e.g.,inert diluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. E.g., a time delay material such as glyceryl monostearateor glyceryl distearate alone or with a wax may be employed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, e.g., 0.075to 20% w/w. When formulated in an ointment, the active ingredients maybe employed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base.

If desired, the aqueous phase of the cream base may include a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400) and mixtures thereof. Thetopical formulations may desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of Formula I compounds contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

The pharmaceutical compositions of compounds of Formula I may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. E.g., atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. E.g., an aqueous solution intended forintravenous infusion may contain from about 3 to 500 μg of the activeingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, e.g. about 0.5to 10% w/w, e.g. about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising e.g. cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size e.g. in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,e.g. sealed ampoules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, e.g. water, for injection immediately prior to use.Extemporaneous injection solutions and suspensions are prepared fromsterile powders, granules and tablets of the kind previously described.Preferred unit dosage formulations are those containing a daily dose orunit daily sub-dose, as herein above recited, or an appropriate fractionthereof, of the active ingredient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

The compounds of Formula I may be employed alone or in combination withother therapeutic agents for the treatment of a disease or disorderdescribed herein, such as a hyperproliferative disorder (e.g., cancer).In certain embodiments, a compound of Formula I is combined in apharmaceutical combination formulation, or dosing regimen as combinationtherapy, with a second compound that has anti-hyperproliferativeproperties or that is useful for treating a hyperproliferative disorder(e.g., cancer). The second compound of the pharmaceutical combinationformulation or dosing regimen preferably has complementary activities tothe compound of Formula I such that they do not adversely affect eachother. Such compounds are suitably present in combination in amountsthat are effective for the purpose intended. In one embodiment, acomposition of this invention comprises a compound of Formula I, incombination with a chemotherapeutic agent such as described herein.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

In a particular embodiment of anti-cancer therapy, a compound of FormulaI, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite,or pharmaceutically acceptable salt or prodrug thereof, may be combinedwith other chemotherapeutic, hormonal or antibody agents such as thosedescribed herein, as well as combined with surgical therapy andradiotherapy. Combination therapies according to the present inventionthus comprise the administration of at least one compound of Formula I,or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof, and the use of atleast one other cancer treatment method. The amounts of the compound(s)of Formula I and the other pharmaceutically active chemotherapeuticagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

Metabolites of Formula I Compounds

Also falling within the scope of this invention are the in vivometabolic products of Formula I described herein. Such products mayresult e.g. from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound. Accordingly, the inventionincludes metabolites of compounds of Formula I, including compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, may be useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the diseases anddisorders described above is provided. The kit comprises a containercomprising a compound of Formula I. The kit may further comprise a labelor package insert, on or associated with the container. The term“package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products, that contain informationabout the indications, usage, dosage, administration, contraindicationsand/or warnings concerning the use of such therapeutic products.Suitable containers include, e.g., bottles, vials, syringes, blisterpack, etc. The container may be formed from a variety of materials suchas glass or plastic. The container may hold a compound of Formula I orII or a formulation thereof which is effective for treating thecondition and may have a sterile access port (e.g., the container may bean intravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle). At least one active agent in thecomposition is a compound of Formula I. The label or package insertindicates that the composition is used for treating the condition ofchoice, such as cancer. In addition, the label or package insert mayindicate that the patient to be treated is one having a disorder such asa hyperproliferative disorder, neurodegeneration, cardiac hypertrophy,pain, migraine or a neurotraumatic disease or event. In one embodiment,the label or package inserts indicates that the composition comprising acompound of Formula I can be used to treat a disorder resulting fromabnormal cell growth. The label or package insert may also indicate thatthe composition can be used to treat other disorders. Alternatively, oradditionally, the article of manufacture may further comprise a secondcontainer comprising a pharmaceutically acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of Formula I and, if present, the second pharmaceuticalformulation. E.g., if the kit comprises a first composition comprising acompound of Formula I, and a second pharmaceutical formulation, the kitmay further comprise directions for the simultaneous, sequential orseparate administration of the first and second pharmaceuticalcompositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I or II, such as tablets orcapsules. Such a kit preferably includes a number of unit dosages. Suchkits can include a card having the dosages oriented in the order oftheir intended use. An example of such a kit is a “blister pack”.Blister packs are well known in the packaging industry and are widelyused for packaging pharmaceutical unit dosage forms. If desired, amemory aid can be provided, e.g. in the form of numbers, letters, orother markings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to one embodiment, a kit may comprise (a) a first containerwith a compound of Formula I contained therein; and optionally (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound with anti-hyperproliferative activity. Alternatively, oradditionally, the kit may further comprise a third container comprisinga pharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

Preparation of Formula I Compounds

Benzoxepin compounds of Formula I may be synthesized by synthetic routesthat include processes analogous to those well-known in the chemicalarts, particularly in light of the description contained herein. Thestarting materials are generally available from commercial sources suchas Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), orBeilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database).

In certain embodiments, compounds of Formula I may be readily preparedusing well-known procedures to prepare benzoxepin compounds (Sekhar etal (1989) Sulfur Letters 9(6):271-277; Katsura et al (2000 J. Med. Chem.43:3315-3321; Rueeger et al (2004) Biorganic & Med. Chem. Letters14:2451-2457; Reiter et al (2007) Biorganic & Med. Chem. Letters17:5447-5454; Banaszak et al (2006) Tetrahedron Letters 47:6235-6238)and other heterocycles, which are described in: ComprehensiveHeterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997,e.g. Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985);Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung,40(12):1328-31, (1990).

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, e.g. 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds, or pharmaceutically acceptable salts thereof.

For illustrative purposes, the General Procedures show general methodswhich may be applied for preparation of Formula I compounds, as well askey intermediates. The Figures and Examples sections contain moredetailed description of individual reaction steps. Those skilled in theart will appreciate that other synthetic routes may be used tosynthesize the inventive compounds. Although certain starting materialsand routes are depicted in the Schemes, General Procedures and Examples,other similar starting materials and routes can be substituted toprovide a variety of derivatives and/or reaction conditions. Inaddition, many of the compounds prepared by the methods described belowcan be further modified in light of this disclosure using conventionalchemistry well known to those skilled in the art.

In preparing compounds of Formulas I, protection of remote functionality(e.g., primary or secondary amine) of intermediates may be necessary.The need for such protection will vary depending on the nature of theremote functionality and the conditions of the preparation methods.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, Third Ed., 1999.

Methods of Separation

In the methods of preparing the compounds of this invention, it may beadvantageous to separate reaction products from one another and/or fromstarting materials. The desired products of each step or series of stepsis separated and/or purified (hereinafter separated) to the desireddegree of homogeneity by the techniques common in the art. Typicallysuch separations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, e.g.: reverse-phase and normal phase; size exclusion; ionexchange; high, medium and low pressure liquid chromatography methodsand apparatus; small scale analytical; simulated moving bed (SMB) andpreparative thin or thick layer chromatography, as well as techniques ofsmall scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. E.g., boiling point and molecular weight indistillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

General Preparative Procedures

General Procedure A

Benzoxepin intermediates,4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate esters, A-1 can beselectively brominated with N-bromosuccinimide (NBS) in DMF to give9-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate estersA-2.

General Procedure B

Benzoxepin carboxylic acid intermediates B-1 are converted to the acidchloride B-2 and reacted with primary or secondary amines withtriethylamine, DMAP, and solvent such as dichloromethane. Reaction witha primary amine may be followed by N-alkylation, e.g. with methyl iodideand sodium hydride, to generate4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide B-3.

E.g., to a suspension of carboxylic acid (0.4 mmol) in anhydrousdichloromethane, is added oxalyl chloride (0.7 mmol) and one drop ofdimethyl formamide. After 30 minutes, concentrate in-vacuo. Residue isdissolved in acetonitrile, and potassium carbonate (0.9 mmol) and anamine, e.g. aniline (0.48 mmol) are added. Reaction mixture is stirredovernight at room temperature before diluting with water andethylacetate. Organic phase is dried (MgSO₄) and concentrated in-vacuo.

Alternatively, other active esters of benzoxepin carboxylic acidintermediates B-1 can be formed as anhydrides, acyl imidazolides, acylazides, and NHS esters to react with amines. Also, benzoxepin carboxylicacid intermediates B-1 can be coupled with amines by in situ formationof active ester intermediates under the broad array of known peptidecoupling reagents and methodology.

E.g., to a solution of the carboxylic acid (1 eq) in DMF (6 mL) is addedthe amine (1.3 eq), HATU (1.3 eq) and diisopropylethyl amine (1.3 eq+1.3eq for each HCl salt of the amine) and the reaction stirred at roomtemperature for 16 h. The mixture is partitioned between ethyl acetateand water. The organic layer was washed with brine (3×), dried (MgSO₄),reduced in vacuo and purified on silica to give the final amide.

General Procedure C

9-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamideintermediates C-1 are carbonylated with carbon monoxide under highpressure with palladium catalysis, such as Pd(OAc)₂, and an alcohol,such as methanol to give the carboxamide intermediate C-2.Saponification with lithium hydroxide, sodium hydroxide or other aqueousbase to the 8-carboxylic acid intermediate, followed by coupling of aprimary or secondary amine with a coupling reagent, such as HATU or DCCgives the 9-carboxamide intermediate C-3.

Alternatively, intermediate C-3 may be prepared directly from bromointermediate C-1 by aminocarbonylation, following the procedures ofWannberg et al (2003) J. Org. Chem. 68:5750-5753.

General Procedure D

9-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamideintermediates D-1 are aminated with primary or secondary amines(HNR¹⁰R¹¹) or amides (H₂NC(═O)R¹⁰), palladium complexes such asPd₂(dba)₃, catalysts such as xantphos and BINAP, alkoxides such asNaOt-Bu or carbonates such as cesium carbonate, in toluene or dioxane,and heating to give aminated products D-2.

General Procedure E

8-Bromo-4H-thieno[3,2-c]chromene-2-carboxamide intermediates E-1 areformylated with butyl lithium and dimethylformamide (DMF) to give E-2which is reductively aminated with a hydride such as sodiumacetoxyborohydride and a primary or secondary amine (HNR¹⁰R¹¹).

FIGS. 1-15 show general methods for preparation of Formula I benzoxepincompounds and intermediates.

FIG. 1 shows a synthetic route to2-Bromo-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene 5.

FIG. 2 shows a synthetic route to8-Amino-4,5-dihydro-6-oxa-1-thia-9-aza-benzo[e]azulene-2-carboxylic acid(2-chloro-phenyl)-amide 15 and amide intermediates 16.

FIG. 3 shows a synthetic route to8-Chloro-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1,9-diaza-benzo[e]azulene21.

FIG. 4 shows a synthetic route to8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 from8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25

FIG. 5 shows a synthetic route to8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene235, and sulfonamides 32, 445, 455.

FIG. 6 shows a synthetic route to 36 and 38 from8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene235

FIG. 7 shows a synthetic route to 39, 40, and 41 from8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene235

FIG. 8 shows a synthetic route to 47 from 24

FIG. 9 shows a synthetic route to 51 from 27

FIG. 10 shows a synthetic route to 56 from 53 and 27

FIG. 11 shows a synthetic route to 62 from 58 and 27

FIG. 12 shows a synthetic route to 66a and 66b from 63

FIG. 13 shows a synthetic route to 69, 70, and 71 from 64

FIG. 14 shows a synthetic route to 75

FIG. 15 shows a synthetic route to 76 and 77

EXAMPLES

The chemical reactions described in the Examples may be readily adaptedto prepare a number of other PI3K inhibitors of the invention, andalternative methods for preparing the compounds of this invention aredeemed to be within the scope of this invention. E.g., the synthesis ofnon-exemplified compounds according to the invention may be successfullyperformed by modifications apparent to those skilled in the art, e.g.,by appropriately protecting interfering groups, by utilizing othersuitable reagents known in the art other than those described, and/or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

In the Examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Sigma Aldrich Chemical Company, andwere used without further purification unless otherwise indicated. Thereactions set forth below were conducted generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried. Columnchromatography was conducted on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SEP PAK®cartridge (Waters). ¹H NMR spectra were obtained at 400 MHz indeuterated CDCl₃, d₆-DMSO, CH₃OD or d₆-acetone solutions (reported inppm), using chloroform as the reference standard (7.25 ppm). When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz). Chemical structures were namedaccording to: vendor designation; IUPAC convention; ChemDraw Ultra,Version 9.0.1, CambridgeSoft Corp., Cambridge Mass.; or Autonom 2000Name, MDL Inc. It is recognized by those skilled in the art that acompound may have more than one name, according to differentconventions.

Example 1 4,8-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

Step 1: ethyl 4-(3-bromophenoxyl)butanoate

Solid 3-bromophenol (10.0 g, 58 mmol) was added portion wise to astirred suspension of K₂CO₃ in acetone (100 mL) at room temperature.Sodium iodide (NaI, 1.0 g) was added, followed by ethyl-4-bromobutyrate(9.2 mL, 64 mmol). The reaction mixture was heated at 80° C. overnight,cooled to room temperature, diluted with water and extracted withethylacetate to give ethyl 4-(3-bromophenoxyl)butanoate.

Step 2: 4-(3-bromophenoxy)butanoic acid

Ethyl 4-(3-bromophenoxyl)butanoate was taken up in 100 mL THF and 50 mLwater and treated with lithium hydroxide LiOH (hydrate, 4.9 g). Thewhole was heated at 50° C. for 2 days. The mixture was cooled to roomtemperature and acidified to pH 1 with 2N HCl. The aqueous was extractedwith ethylacetate. The combined organics were washed with brine anddried over sodium sulfate to give crude 4-(3-Bromophenoxy)butanoic acidas a sticky solid. ¹H NMR (DMSO-d6, 500 MHz) 7.24 (m, 1H), 7.13 (m, 1H),7.11 (m, 1H), 6.95 (m, 1H), 3.99 (m, 2H), 2.37 (m, 2H), 1.94 (m, 2H).

Step 3: 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To a stirred suspension of polyphosphoric acid (PPA, ca. 60 g) andcelite (ca. 40 g) in 100 mL toluene was added crude4-(3-bromophenoxy)butanoic acid (ca. 58 mmol) in one portion, 10 mLtoluene rinse. The resultant suspension was heated at 110° C. for 5 hr.The toluene was decanted through a plug of celite and the remainingslurry was washed repeatedly with toluene and ethylacetate. The eluentwas concentrated and purified by flash column chromatography (4:1hex:EtOAc) to give 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (7 g, ca.50% yield). ¹H NMR (DMSO-d6, 500 MHz) 7.55 (d, J=8.5 Hz, 1H), 7.37 (d,J=1.5 Hz, 1H), 7.35 (dd, J=8.5, 1.5 Hz, 1H), 4.24 (t, J=6.5 Hz, 2H),2.79 (t, J=7.0 Hz, 2H), 2.14 (m, 2H).

Step 4: 4,8-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To a stirred solution of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one(3.10 g; 12.8 mmol) in Et₂O at 0° C. was added Br₂ (625 μl; 12.2 mmol)and the reaction mixture was allowed to warm to r.t. over 2 h. Volatileswere evaporated and the residue purified by flash column chromatography(0-20% EtOAc in hexanes) to give4,8-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one as a colorless solid(4.0 g, 96% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.21 (m, 2H), 7.55(d, J=8.0, 1H), 4.87 (app. t, J=5.2, 2H), 4.33-4.39 (m, 1H), 4.09-4.16(m, 1H), 2.78-2.91 (m, 1H), 2.40-2.49 (m, 1H).

Example 28-Bromo-2-ethynyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Step 1:8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidethyl ester

To a stirred solution of 4,8-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one(2.17 g; 6.8 mmol) in EtOH (70 ml) was added ethyl thiooxamate (2.72 g;20.4 mmol) and the reaction mixture was heated at reflux temperatureover 4 d. The reaction mixture was concentrated and the residue purifiedby flash column chromatography (0-20% EtOAc in hexanes) to give8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidethyl ester as a yellow solid (1.08 g, 45% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.36 (d, J=8.4, 1H), 7.16-7.22 (m, 2H), 4.42 (q, J=7.2, 2H),4.31 (app. t, J=5.2, 2H), 3.32 (app. t, J=5.2, 2H), 1.38 (t, J=7.2, 3H).

Step 2:8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid

To a stirred solution of8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidethyl ester in THF (10 ml) and MeOH (5 ml) was added a solution of NaOH(117 mg, 2.9 mmol) in water (2 ml). The reaction mixture was stirred atroom temperature for 2 h upon which time it was acidified with 2M HCl.The aqueous was extracted with CH₂Cl₂ and the combined organics dried(MgSO₄) and concentrated to give8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidas a colorless solid (396 mg; 83%). ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d,J=8.4, 1H), 7.19-7.24 (m, 2H), 4.33 (t, J=5.2, 2H), 3.36 (t, J=5.2, 2H).

Step 3:(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-methanol

Lithium tetrahydroaluminate (0.363 g, 9.56 mmol) was suspended intetrahydrofuran (30 mL) and cooled to 0° C. A solution of8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(1.04 g, 3.19 mmol) in tetrahydrofuran (1 mL) was then added dropwiseover a 10 min period. The resulting reaction mixture was stirred whilewarming to r.t. for 12 h. LCMS indicated that the reaction wascompletely converted with a minor uncharacterized impurity present(<5%). The reaction was quenched by diluting with saturated Rochelle'ssalt solution and EtOAc (1:1, 200 mL). The mixture was stirred veryvigorously until the phases separated. The layers were then partitionedand the aqueous layer was extracted with EtOAc (3×). The combinedorganic portions were dried over MgSO₄, filtered and concentrated. Thecrude residue was purified by ISCO chromatography (40 g column, 0-75%EtOAc/heptane) to provide 0.63 g (63% yield) of(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-methanol.LC/MS (ESI+): m/z 313.2 (M+H).

Step 4:8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbaldehyde

Oxalyl chloride (0.24 mL, 2.9 mmol) was added dropwise to a solution ofmethyl sulfoxide (0.20 mL, 2.9 mmol) in dry dichloromethane (5 mL) andthe resulting mixture was stirred 5 min. A solution of(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-methanol(0.60 g, 1.9 mmol) in dichloromethane (5 mL) was added portion-wise tothe mixture and followed immediately by triethylamine (0.8 mL, 5.8mmol). The reaction mixture was stirred and monitored by thedisappearance of the starting alcohol. The reaction was quenched by theaddition of water and EtOAc. The aqueous layer was extracted with EtOAc,dried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified by ISCO chromatography (0-50% EtOAc/heptane) to provide8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbaldehyde(0.41 g, 69% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 8.39 (dd,J=8.5, 6.8, 1H), 7.37-7.15 (m, 2H), 4.38 (m, 2H), 4.12 (d, J=9.5, 1H)

Step 5: 8-Bromo-2-ethynyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbaldehyde(0.688 g, 2.2 mmol) was dissolved in methanol (8 mL) and methyl2-diazo-2-(dimethoxyphosphoryl)acetate (0.923 g, 4.44 mmol) was addedfollowed by potassium carbonate (0.613 g, 4.44 mmol). The resultingmixture was stirred 12 h at ambient temperature and quenched by theaddition of sat. NH₄Cl aqueous solution and stirred 5 min. Diluted withH₂O and EtOAc, extracted the aqueous layer with EtOAc (2×) and thecombined organic portions were washed with brine. Dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by ISCOchromatography (24 g column, 0-25% EtOAc/heptane) to provide8-Bromo-2-ethynyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as anoil (0.26 g, 38% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=8.5, 1H),7.31-7.18 (m, 2H), 4.37 (t, J=5.1, 2H), 3.49 (s, 1H), 3.33 (t, J=5.1,2H)

Example 39-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid

Step 1: 1-(5-bromo-2-(2-bromoethoxyl)phenyl)ethanone

To a stirred solution of 5′-bromo-2′-hydroxyacetophenone (10 g, 46.5mmol) in methyl ethyl ketone (100 mL) was added K₂CO₃ (13.5 g, 97.7mmol) followed by 1,2-dibromoethane (20 mL, 232.5 mmol). The reactionmixture was heated at a mild reflux temperature (ca. 80° C.) for 16 h atwhich point the reaction flask was cooled to room temperature. Theresultant solids were filtered off and the solvent removed by rotaryevaporation under reduced pressure. The residue was dissolved inEt₂O/EtOAc (4:1, 500 mL) and the precipitated solid (the alkylationdimer) was removed by filtration. The filtrate was washed with 2 N NaOH(100 mL) and the organic portion was dried over Na₂SO₄ and concentratedin vacuo to give crude 1-(5-bromo-2-(2-bromoethoxyl)phenyl)ethanone(8.07 g, 55%)

Step 2: 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To a slurry of NaH (60% dispersion in mineral oil) (1.48 g, 37.1 mmol)in THF (˜50 mL) at room temperature was added1-(5-bromo-2-(2-bromoethoxyl)phenyl)ethanone (8.07 g, 25.1 mmol). Thereaction mixture was slowly heated to reflux and allowed to stir for 20h. The solvent was removed under vacuum pressure and the concentratedresidue was absorbed onto silica gel and purified by columnchromatography (4:1 ethyl acetate/petroleum ether). The product wasafforded as a yellow oil after the solvents were removed, providing 4.22g (70%) of 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one. ¹H NMR (CDCl₃) δ7.87 (d, J=2.6 Hz, 1H), 7.50 (dd, J=2.6, 8.1 Hz, 1H), 6.97 (d, J=8.8 Hz,2H), 4.24 (t, J=6.6 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.15-2.29 (m, 2H).

Step 3: 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3 g, 12 mmol) in ether(110 mL) was added bromine (0.7 mL, 14 mmol) and allowed to stir at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure and purified via ISCO chromatography (hexane to 20%hexane in EtOAc over 45 minutes). Collected fractions and concentratedto give 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3.53 g, 89%).¹H NMR (500 MHz, CDCl₃) δ 7.86 (d, J=2.5, 1H), 7.52 (dt, J=28.5, 14.2,1H), 6.97 (d, J=8.7, 1H), 4.95 (dd, J=7.6, 6.8, 1H), 4.53-4.36 (m, 1H),4.17 (ddd, J=12.8, 9.9, 4.4, 1H), 3.04-2.84 (m, 1H), 2.52 (ddt, J=14.7,7.8, 4.5, 1H)

Step 4:9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidethyl ester

To 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3.4 g, 11 mmol) andethyl thioamidooxalate (4.2 g, 32 mmol) was added ethanol (81 mL) andheated at reflux (at 80° C.) for 4 days. The reaction mixture was cooledto room temperature and cooled in an ice bath. The precipitate wascollected by filtration to give9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidethyl ester (2.59 g, 69%). LC/MS (ESI+): m/z 355 (M+H).

Step 5:9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid

To 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid ethyl ester (2.52 g, 7.11 mmol) and LiOH (1.53 g, 36.6 mmol) wasadded THF (6.5 mL) and water (6.5 mL) and allowed to stir at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure to remove the THF. The reaction mixture was dilutedwith EtOAc and 1 N HCl and warmed in a water bath to solubilize thesolid. The layers were separated and the organic extract was washedsequentially with water and brine. The combined organic extracts weredried over MgSO₄ and filtered. The filtrate was concentrated underreduced pressure to give9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid. LC/MS (ESI+): m/z 327 (M+H)

Example 49-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide

9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2.4 g, 7.4 mmol) was dissolved in N,N-Dimethylformamide (DMF, 50 mL,600 mmol). Added N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uraniumHexafluorophosphate (3.1 g, 8.1 mmol) and N,N-Diisopropylethylamine (6.4mL, 37 mmol) and let stir for 10 minutes. Added2-(isopropylamino)ethanol (1.5 g, 15 mmol) and let the reaction stir for2 hours. More N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uraniumHexafluorophosphate was added to the reaction (2.8 g, 7.4 mmol) and letthe reaction stir for another 3 hours. Reaction was complete by LCMS.Concentrated in vacuo and flash purified on the ISCO 0 to 50% ethylacetate in hexanes two times to give9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (2.05 g, 68% yield).

Example 59-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide

To 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2.13 g, 6.53 mmol) in THF (22 mL) was added ammonium chloride(1.40 g, 26.1 mmol), DIEA (2.27 mL, 13.1 mmol), and then HATU (2.73 g,7.18 mmol). The reaction mixture was allowed to stir at room temperaturefor 16 h. The reaction mixture was diluted with sodium bicarbonate andethyl acetate. The mixture was filtered and the filtrate was extractedwith EtOAc. The combined organic extracts were washed with water, brine,dried over MgSO₄, filtered, and concentrated under reduced pressure togive 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid amide (2.12, quantitative yield). LC/MS (ESI+): m/z 327 (M+H)

Example 69-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid amide (2.12 g, 6.52 mmol) in toluene (35 mL) was added1,1-dimethoxy-N,N-dimethylmethaneamine (7.3 mL, 54.8 mmol). The reactionmixture was allowed to stir and heat to 95° C. for 3 hours. The reactionmixture was cooled to room temperature and concentrated under reducedpressure. The crude residue was treated with a suspension ofisopropylhydrazine hydrochloride (0.865 g, 7.82 mmol) in acetic acid(18.5 mL) and water (2.35 mL). The mixture was heated in a sealed vialat 95° C. overnight. The reaction mixture was slowly poured onto amixture of ice, sodium bicarbonate, and ethyl acetate. The mixture wasextracted with ethyl acetate carefully after bubbling subsided. Thelayers were separated and the organic extract was washed sequentiallywith water and brine. The combined organic extracts were dried overMgSO₄, filtered, and concentrated under reduced pressure. The cruderesidue was dissolved in a minimal amount of ethyl acetate and purifiedvia ISCO chromatography (hexane to 20% hexane in EtOAc over 45 minutes).Collected fractions and concentrated to give9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.897 g, 35%). LC/MS (ESI+): m/z 393 (M+H). ¹H NMR (400 MHz, CDCl₃) δ8.51 (d, J=2.5, 1H), 7.93 (s, 1H), 7.34 (dd, J=8.6, 2.5, 1H), 6.96 (d,J=8.6, 1H), 5.84 (dt, J=13.5, 6.8, 1H), 4.40 (t, J=5.0, 2H), 3.42 (t,J=5.0, 2H), 1.66 (d, J=6.6, 6H)

Example 7 (Z)-8-bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde

Phosphorus oxychloride, POCl₃ (1.88 mL, 20.8 mmol) was added dropwise toDMF (5 mL) at 0° C. After 30 min a solution of8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (2.0 g, 8.3 mmol) in 8 mLDMF was added dropwise. The reaction mixture was allowed to reach roomtemperature to stir 2 hr, then poured slowly over rapidly stirred icewater. The aqueous phase was extracted with ethylacetate and thecombined organics were washed with brine, dried over sodium sulfate andconcentrated to give(Z)-8-bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde.

Example 8 methyl8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate

(Z)-8-Bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde 9 wasdissolved in 10 mL DMF and treated sequentially with potassium carbonate(2.20 g, 16.6 mmol) and methyl thioglycolate (0.83 mL). The whole washeated at 50° C. overnight, cooled to room temperature, diluted withwater and extracted with ethylacetate. The combined organics were washedwith brine, dried over sodium sulfate and concentrated. The cruderesidue was purified by flash column chromatography (20-50% ethylacetatein hexanes) to give 2.20 g (78% yield) 10 as a colorless solid. ¹H NMR(DMSO-d6, 500 MHz) 7.70 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.31-7.28 (m,2H), 4.32 (t, J=5.0 Hz, 2H), 3.84 (s, 3H), 3.21 (t, J=5.0 Hz, 2H).

Example 9 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylicacid 11

Methyl 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate 10was treated with lithium hydroxide in water and tetrahydrofuran (THF) togive 11.

Example 10 10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylicacid

Step 1: 2-Iodo-3-(2-thiophen-3yl-ethoxy)-pyridine

To a solution containing 2-iodo-3-hydroxypyridine (1.85 g, 8.37 mmol),2-(3-thienyl)ethanol (1.20 mL, 10.9 mmol), and triphenylphosphine (2.85g, 10.9 mmol) in tetrahydrofuran (46.2 mL, 5.70 mmol) was addeddiisopropyl azodicarboxylate (2.14 mL, 10.9 mmol) dropwise. The reactionmixture was stirred at room temperature for 18 h. The reaction mixturewas concentrated and purified by flash chromatography EtOAc/Hex (0-100%)eluted at 30% to give 2-Iodo-3-(2-thiophen-3yl-ethoxy)-pyridine (yield90%). MS: (ESI+) 332.2

Step 2: 10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine

To a solution of 2-iodo-3-(2-thiophen-3yl-ethoxy)-pyridine (1.15 g, 4.05mmol) in N,N-dimethylformamide (60.9 mL, 787 mmol) was added potassiumcarbonate (2.80 g, 20.2 mmol), triphenylphosphine (212 mg, 0.809 mmol),tetraethylammonium chloride (4.05 mmol) and palladium acetate (90.8 mg,0.405 mmol). The reaction mixture was stirred at 90° C. 8 h. Thereaction mixture was diluted with DCM then filtered through celite. Thefiltrate was concentrated and wash water. The crude product was purifiedby flash chromatography EtOAc/Hex (0-100%) product eluted at 30% to give10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine (yield 60%). MS: (ESI+)204.3

Step 3: 2-bromo-(10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine)

10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine (1.73 g, 8.51 mmol) wasdissolved in methylene chloride (20 mL, 400 mmol) and acetic acid (20mL, 400 mmol) and cooled to 0° C. N-Bromosuccinimide (1.67 g, 9.36 mmol)was added portionwise to the mixture. The reaction was stirred for 18hours. Solvents were rotary evaporated, the residue partitioned betweenethyl acetate and sat. sodium carbonate aqueous solution. The organiclayer was washed with water, brine and dried over sodium sulfate. Afterrotary evaporation the crude product was chromatographed on Isco(hexane-EtOAc gradient, 0-100%) eluted 20% EtOAc to give2-bromo-(10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine). MS: (ESI+)283.2

Step 4: 10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid

To a solution of2-bromo-(10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine) (0.700 g, 2.48mmol) in tetrahydrofuran (25.0 mL, 308 mmol) was added 2.50 M ofn-butyllithium in hexane (1.19 mL) dropwise at −78° C. The reactionmixture was stirred at −78° C. for 1 h. The mixture was added to aslurry of dry ice in THF (15 ml) then stirred 2 h. The reaction mixturewas quenched with water then slightly basified and extracted EtOAc (2×).The aqueous layer was acidified to pH 2 then extracted with DCM (2×).The organic layers were combined and concentrated to give10-aza-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid (yield62%). MS: (ESI+) 248.3

Example 119-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylicacid amide

Step 1: 6-chloro-2-iodopyridin-3-ol

To solution of 6-chloro-pyridin-3-ol (112 g, 868 mmol) in THF (800mL)/Water (800 mL) was added sodium carbonate (92.0 g, 1.736 mol) andiodine (244.2 g, 1.04 mol). The reaction mixture was stirred rt 4 h. Theaqueous layer containing product was separated and washed with hexane(400 mL×2). The aqueous layer was neutralized to pH=7 with HCl and thenextracted EtOAc (500 mL×4). The combined organic layers were dried overNa₂SO₄, and filtered. The filtrate was concentrated to the crudeproduct, which was washed with EtOAc to afford 163 g of6-chloro-2-iodopyridin-3-ol, yield: 75%. ¹H NMR (DMSO, 400 MHz): δ11.13(s, 1H, OH), 7.31 (dd, J=8.4, 12.8 Hz, 2H).

Step 2: 2-(thiophen-3-yl)ethanol

Tetrahydrofuran (200 mL) was added to LiAlH₄ (4.56 g, 0.12 mol) and themixture was stirred at 0° C. 2-(thiophen-3-yl) acetic acid (14.2 g, 0.1mol) in THF (100 mL) was added dropwise at this temperature. After theaddition, the reaction mixture was stirred at 0° C. for further 2 hours.To the reaction mixture was added EtOAc (200 mL) slowly and then 5 mL ofwater. The suspension was filtered though ceilite, the filtrate wasdried over anhydrous sodium sulfate and concentrated to dryness toafford 2-(thiophen-3-yl)ethanol (12.44 g, yield: 99%). ¹H NMR (MeOD, 400MHz): δ5.92-5.87 (m, 1H), 5.69-5.66 (m, 1H), 5.57 (s, 1H) 2.90 (d,J=14.0 Hz, 1H), 2.38 (d, J=14 Hz, 1H), 1.55-1.42 (m, 2H).

Step 3: 6-chloro-2-iodo-3-(2-(thiophen-3-yl)ethoxy)pyridine

To a solution 6-chloro-2-iodopyridin-3-ol (6.75 g, 26.4 mmol),2-(3-thienyl) ethanol (3.79 mL, 34.4 mmol), and triphenylphosphine (9.01g, 34.4 mmol) in tetrahydrofuran (140 mL) was added diisopropylazodicarboxylate (6.76 mL, 34.4 mmol) dropwise. The reaction mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated and purified by column on silica gel (eluted atEtOAc/Hexanes=1:20) to give 5.5 g of6-chloro-2-iodo-3-(2-(thiophen-3-yl)ethoxy)pyridine. Yield: 58%. ¹H NMR(DMSO, 400 MHz): δ7.50-7.43 (m, 3H), 7.34 (d, J=1.6 Hz, 1H), 7.17 (d,J=4.8 Hz, 1H), 4.29 (t, J=6.4 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H). LC-MS(ESI): m/z=366 [M+H]⁺

Step 4: 9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene

To a solution of 6-chloro-2-iodo-3-(2-(thiophen-3-yl)ethoxy)pyridine(9.14 g, 25.0 mmol) in acetonitrile (150 mL) was addedtetraethylammonium chloride (4.14 g, 25.0 mmol), potassium carbonate(6.91 g, 50.0 mmol) and triphenylphosphine (1.31 g, 5.00 mmol) Thereaction mixture was degassed and then charged with N₂ three times.Palladium acetate (0.561 g, 2.50 mmol) was added to the reactionmixture. The reaction mixture was stirred under N₂ at 80° C. for 3 h.The reaction mixture was diluted with DCM then filtered through celite.The filtrate was concentrated to get the crude product, which waspurified by column on silica gel (EtOAc/Hexanes=1:10) to afford 54.6 gof 9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (Yield:89%)¹H NMR (DMSO, 400 MHz): δ7.60 (d, J=5.2 Hz, 1H), 7.48 (d, J=6.0 Hz,1H), 7.26 (d, J=6.0 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 4.32 (t, J=4.4 Hz,2H), 3.20 (t, J=4.4 Hz, 2H). LC-MS (ESI): m/z=238 [M+H]⁺

Step 5: 2-Bromo-9-chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene

9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.33 g, 18.2mmol) was dissolved in methylene chloride (40 mL, 600 mmol)/acetic acid(40 mL, 700 mmol). The solution was cooled down to 0-5° C. and added asolution of N-Bromosuccinimide (3.57 g, 20.0 mmol) in 10 mL of DCMslowly. The reaction mixture was stirred for 18 hours. After removal ofthe solvents, the residue was partitioned between ethyl acetate andsaturated sodium carbonate aqueous solution. The organic layer waswashed with water, brine and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated to give2-Bromo-9-chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene. ¹HNMR(DMSO, 400 MHz): δ 7.48 (d, J=8.4 Hz, 1H, ArH), 7.28 (d, J=8.4 Hz, 1H,ArH), 7.18 (s, 1H, ═CH), 4.32 (t, J=4.4 Hz, 2H, CH₂), 3.17 (t, J=4.4 Hz,2H, CH₂).

Step 6:9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylicacid

To a solution of2-Bromo-9-chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (0.440g, 1.56 mmol) in tetrahydrofuran (24.0 mL, 296 mmol) was added 2.50 M ofn-Butyllithium in hexane (0.748 mL) dropwise at −78° C. The reactionmixture was stirred at −78° C. for 1 h. The mixture was bubbled by driedCO₂ gas for 0.5-1 hour. The reaction mixture was quenched with waterthen slightly basified and extracted EtOAc (2×). The aqueous layer wasacidified to pH=2 then extracted with DCM (2×) to yield 0.34 g of9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylicacid (Yield: 76%)¹H NMR (DMSO, 400 MHz): δ13.28 (br s, 1H, COOH),7.64-7.35 (m, 3H, ArH), 4.36 (t, J=4.4 Hz, 2H, CH₂), 3.24 (t, J=4.4 Hz,2H, CH₂).

Step 7:9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylicacid amide

A mixture of9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylicacid (24.6 g, 87.5 mmol), N,N-Diisopropylethylamine (68 g, 525 mmol),ammonium chloride (18.7 g, 350 mmol) and HATU (66.5 g, 175 mmol) inN,N-Dimethyl-formamide (200 mL) was stirred at r.t. for overnight. Thereaction mixture was added saturated sodium bicarbonate. After filtered,the filtrate was concentrated to 23 g of9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylicacid amide (yield: 94%)¹H-NMR (DMSO, 400 MHz): δ7.96 (d, J=18.4 Hz, 1H),7.56 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J=4.8 Hz,1H), 4.33 (t, J=4.8 Hz, 2H), 3.19 (t, J=4.8 Hz, 2H). LC-MS (ESI):m/z=281 [M+H]⁺

Example 129-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene

To a suspension of9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylicacid amide (22 g, 76.8 mmol) in dry toluene (250 mL) was added DMA-DMF(56.1 g, 471.4 mmol). The resulting mixture was heated to 90° C. for 2h. After removal of the solvent and excess of DMA-DMF, the residue (13.6g, 94.3 mmol) was dissolved in acetic acid (250 mL) and(2,4-difluorophenyl)hydrazine (16.6 g, 115.2 mmol) was added into themixture. The mixture was stirred at 90° C. for 2 hours. After removal ofthe solvents, the residue was treated with EtOAc-water (500 mL, 5:1(v/v)). The mixture was neutralized with sodium bicarbonate aqueoussolution until pH=7. The suspension was filtered and the solid waswashed with EtOAc (500 mL). The combined organic layers were washed withsaturate sodium bicarbonate aqueous solution (300 mL), dried over sodiumsulfate and filtered. The filtrate was concentrated to the crudeproduct, which was purified by flash column (EtOAc/Hexanes=1:3) to give9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(21.4 g, yield: 67%)¹H NMR (DMSO, 400 MHz): δ8.35 (s, 1H), 7.98-7.48 (m,4H), 7.39 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.38 (t, J=4.4 Hz, 2H), 3.2(t, J=4.4 Hz, 2H). LC-MS (ESI): m/z=417 [M+H]⁺

Example 138-Bromo-2-[1,3,4]oxadiazol-2-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a solution of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(22.2 g, 68.1 mmol) in THF (360 mL) was added(isocyanoimino)triphenylphosphorane (20.6 g, 68.1 mmol) portionwise over1 hour. The resultant mixture was stirred at RT for 18 hours beforebeing concentrated in vacuo and triturated with 1:1 DCM/cyclohexane (200mL). The title compound was collected by filtration as a yellow solid(14.5 g, 61%). LCMS: R_(T)=4.03 min, M+H⁺=350/352.

Example 142-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid

Step 1:8-Bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a solution of8-bromo-2-[1,3,4]oxadiazol-2-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(4.38 g, 12.51 mmol) in pyridine (12 mL) was added isopropylaminehydrochloride (1.38 g, 12.51 mmol). The reaction mixture was heated at160° C. for 30 minutes using microwave irradiation before beingconcentrated in vacuo. The residue was taken up into DCM then washedwith 1M HCl then brine before being dried (Na₂SO₄) and concentrated invacuo. The resultant residue was purified by flash chromatography (SiO₂,gradient 0-3% methanol in DCM then further purified, gradient 0-4% MeOHin EtOAc) to yield the title compound as an orange solid (1.97 g, 40%).LCMS: R_(T)=4.67 min, M+H⁺=391/393.

Step 2:2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid methyl ester

A microwave vial was charged with8-bromo-2-(4-isopropyl-4H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(1.0 g, 2.56 mmol), molybdenum hexacarbonyl (338 mg, 1.28 mmol),Herrmann's catalyst[trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)](122 mg, 0.13 mmol), tri-tert-butylphosphonium tetrafluoroborate (75 mg,0.26 mmol), DBU (0.38 mL, 2.56 mmol), 1,4-dioxan (6 mL) and MeOH (6 mL),flushed with nitrogen then sealed. The mixture was heated at 150° C. for45 minutes using microwave irraditation then filtered through a pad ofCelite®, washing the pad with MeOH. The filtrate was concentrated invacuo and the residue purified by flash chromatography (SiO₂, 0-5% MeOHin EtOAc) to give the title compound as a yellow solid (0.51 g, 54%).LCMS: R_(T)=4.28 min, [M+H]⁺=371

Step 3:[2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methanol

To a solution of2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid methyl ester (620 mg, 1.67 mmol) in THF (12 mL) at 0° C. was addedLiAlH₄ (152 mg, 4.02 mmol). The reaction mixture was stirred for 4 hoursat RT before being quenched with H₂O (0.15 mL), 15% NaOH_((aq)) (0.15mL) and H₂O (0.45 mL). The precipitate was removed by filtration,washing with methanol/DCM, and then the filtrate was concentrated invacuo to yield the title compound as an orange solid (563 mg, 98%).LCMS: R_(T)=3.71 min, [M+H]⁺=343

Step 4:2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde

To a solution of[2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methanol(565 mg, 1.65 mmol) in DCM (20 mL) was added Dess-Martin periodinane(1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 763 mg, 1.80mmol). The reaction mixture was stirred at RT for 2 hours before beingconcentrated in vacuo. The resultant residue was purified by flashchromatography (SiO₂, gradient 0-3% MeOH in DCM) to yield the titlecompound as a white solid (547 mg, 98%). LCMS: R_(T)=4.00 min,[M+H]⁺=341

Step 5:2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid

To a suspension of2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid methyl ester in THF (6 mL) and water (1.5 mL) was added an aqueous1N lithium hydroxide solution (1.0 mL, 1.0 mmol). The reaction mixturewas stirred for 65 hours then an aqueous 1N HCl solution (2 mL) wasadded and the mixture was concentrated in vacuo to remove THF. A smallquantity of MeOH was added to the resultant mixture and the solid wascollected by filtration to give the title compound as an off-white solid(226 mg, 95%). LCMS: R_(T)=3.88 min, [M+H]⁺=357

Example 152-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid methyl ester

The title compound was prepared by a similar procedure to2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid methyl ester using8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 instead of8-bromo-2-(4-isopropyl-4H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.The title compound was isolated as a beige solid (0.61 g, 64%). LCMS:R_(T)=4.71 min, [M+H]⁺=371

Example 16[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methanol

To a suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid methyl ester (778 mg, 2.1 mmol) in THF (20 mL) at −78° C. undernitrogen was added dropwise diisobutyl aluminum hydride (1.5M intoluene, 4.2 mL, 6.3 mmol) and the reaction mixture was stirred at 0° C.for 2 hours. MeOH (10 mL) was added cautiously followed by an aqueous 1Mpotassium sodium tartrate solution (7 mL) at RT. The mixture wasconcentrated in vacuo to remove organic solvent and the aqueous phasewas extracted with DCM (×3). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo to give the title compound as anoff-white solid (713 mg, 99%). LCMS: R_(T)=4.14 min, [M+H]⁺=343

Example 172-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde

To a solution of[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methanol(713 mg, 2.1 mmol) in DCM (25 mL) was added Dess-Martin periodinane(1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 971 mg, 2.3mmol) portionwise. The reaction mixture was stirred for 5 h then dilutedwith DCM (50 mL) and washed with an aqueous saturated sodium bicarbonatesolution (×3). The organic layer was dried (MgSO₄) and concentrated invacuo. The resultant residue was purified by flash chromatography (SiO₂,0-10% EtOAc in DCM) to give the title compound as an off-white solid(736 mg, quant.). LCMS: R_(T)=4.39 min, [M+H]⁺=341

Example 181-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole

To a solution of 4-pyrazole boronic acid pinacol ester (2.0 g, 10.3mmol) in anhydrous DMF (20 mL) was added cesium carbonate (4.03 g, 12.4mmol) and the mixture stirred at RT for 10 minutes.2-(2-Bromoethoxyl)tetrahydro-2H-pyran (1.87 mL, 12.4 mmol) was added intwo portions and the mixture was heated to 70° C. After heating for 18hours the mixture was allowed to cool to RT and partitioned betweenwater (100 mL) and EtOAc (100 mL). The aqueous layer was washed withEtOAc (3×20 mL) and the combined organic layers washed with water (3×100mL) followed by brine, dried (Na₂SO₄) and concentrated in vacuo. Theresultant residue was purified by flash chromatography (SiO₂, gradient0-100% EtOAc in cyclohexane) to afford the title compound (2.15 g, 65%).LCMS: R_(T)=3.97 min, [M+Na]⁺=345

Example 192-(1-Isopropyl-1H-imidazol-2-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Step 1:8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonitrile

To a suspension of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 (11.44 g, 35.2 mmol) in pyridine (115 mL) at −30° C. was addedphosphorus oxychloride (8.4 mL, 91 mmol) dropwise over 10 minutes. Themixture was stirred at −30° C. for 1 hour then allowed to warm to RT andstirred for 2 hours. The mixture was poured into water, stirred for 10minutes and the solid was collected by filtration. The solid wasdissolved in EtOAc and washed with copper sulfate solution. The organiclayer was passed through a silica pad eluting with EtOAc and the solventwas removed in vacuo to afford8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonitrile(7.78 g, 72%). ¹H NMR δ (ppm) (DMSO-d6): 8.25 (1H, d, J=8.61 Hz), 7.38(1H, dd, J=8.68, 2.23 Hz), 7.32-7.30 (1H, m), 4.39 (2H, t, J=5.01 Hz),3.50-3.44 (2H, m)

Step 2:8-Bromo-2-(1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a solution of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonitrile(0.100 g, 0.326 mmol) in 1.0 ml of Methanol was added 25% Sodiummethoxide (0.020 mL, 0.087 mmol) in Methanol. The reaction was stirred 1h rt. Aminoacetaldehyde dimethyl acetal (0.0390 mL, 0.358 mmol) wasadded to the reaction mixture followed by Acetic acid (0.0370 mL, 0.651mmol). The reaction was heated at 50° C. for 1 h and then cooled to rt.Methanol (0.650 mL, 16.0 mmol) and 6.00 M of Hydrogen chloride in Water(0.163 mL) were added, the reaction was heated 100 for 12 h. Thereaction mixture was concentrated then added EtOAc and water. Thecombined organic layers was concentrated to give8-Bromo-2-(1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.MS: (ESI+)=349.1

Step 3:8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboximidicacid ethyl ester hydrochloride

A mixture of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonitrile(4.63 g, 15 mmol) and sodium ethoxide (136 g, 20 mmol) in IMS (45 mL)was heated to 85° C. After heating for 24 hours the mixture was allowedto cool to RT and the solvent was removed in vacuo. The residue wasdissolved 1.25 M HCl in MeOH and stirred at RT for 20 minutes, theresulting solid was collected by filtration to afford the title compound(4.46 g, 76%). ¹H NMR δ (ppm) (DMSO-d6): 9.12 (1H, s), 8.45 (1H, dd,J=8.64, 2.98 Hz), 7.35 (1H, dd, J=8.61, 2.10 Hz), 7.27-7.24 (1H, m),4.38-4.32 (4H, m), 3.39 (2H, t, J=5.03 Hz), 1.38-1.29 (3H, m)

Step 4:8-bromo-N-isopropyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxamidine

A mixture of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboximidicacid ethyl ester hydrochloride (200 mg, 0.513 mmol) and isopropyl-amine(437 μL, 5.13 mmol) in IMS (3 mL) was heated at 140° C. for 90 minutesusing microwave irradiation. The reaction mixture was concentrated invacuo and the residue dissolved in DCM, washed with water and theorganic layer dried (Na₂SO₄). The organic extract was concentrated invacuo and the residue was purified by flash chromatography (SiO₂,gradient 0-30% MeOH in EtOAc) to afford the title compound (878 mg,46%). LCMS: R_(T)=3.26 min, [M+H]⁺=366/368

Step 5:8-Bromo-2-(1-isopropyl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a solution of8-bromo-N-isopropyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxamidine(878 mg, 2.4 mmol) in THF (15 mL) was added chloroacetaldehyde solution(˜50 wt. % in H₂O, 7.53 mL, 47.9 mmol) and aqueous saturated sodiumbicarbonate solution (6 mL) at RT. The mixture was heated to 80° C. withrapid stirring. After heating for 20 hours the mixture was allowed tocool to RT and was extracted with DCM (150 mL). The organic layer waswashed with water followed by brine, dried (Na₂SO₄) and concentrated invacuo. The resultant residue was purified by flash chromatography (SiO₂,gradient 0-100% EtOAc in cyclohexane) to afford the title compound (900mg, 96%). LCMS R_(T)=4.90 min, [M+H]⁺=390/392

Step 6:2-(1-Isopropyl-1H-imidazol-2-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

8-Bromo-2-(1-isopropyl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolewere reacted under Suzuki conditions to give2-(1-Isopropyl-1H-imidazol-2-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.LCMS: R_(T)=4.56 min, [M+H]⁺=506

Example 202-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

The title compound was prepared by a similar method to2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamideusing 2-(2-bromoethoxyl)tetrahydro-2H-pyran instead of 2-bromoacetamideand DMF instead of THF and performing the reaction at 60° C. The titlecompound was isolated as an amber gum (104 mg, 29%). LCMS: R_(T)=3.24,3.35 min, [M+H]⁺=496

Example 212-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

The title compound (110 mg, 45%) was prepared by a similar method to2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneusing9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneinstead of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 and adding potassium iodide (0.2 eq.) to the reactionmixture. LCMS: R_(T)=3.57 min, [M+H]⁺=496

Example 22 3-Azetidine-1-carboxylic acid tert-butyl ester zinc iodide

In a sealed flask were placed zinc dust (1.76 g, 27.1 mmol) and CelpureP65 filter agent (380 mg) and the mixture heated under vacuum with aheat gun for 5 minutes. The flask was purged with argon and allowed tocool to RT. To the mixture was added anhydrous DMA (12 mL), followed bya mixture of TMSCl and 1,2-dibromoethane (0.54 mL, 7:5 v:v), causing alarge exotherm and vigorous effervescence. The reaction mixture wasallowed to cool to RT over 15 minutes before the dropwise addition of3-iodo-azetidine-1-carboxylic acid tert-butyl ester (6.16 g, 21.8 mmol)as a solution in anhydrous DMA (8.5 mL). The reaction mixture wasstirred at RT for 1.5 hours before being filtered to give the titlecompound as a colourless solution in DMA.

Example 233-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester

A solution of8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 (5.67 g, 14.5 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1.18 g, 1.5 mmol) and copper (I) iodide (0.36 g,1.9 mmol) in anhydrous DMA (64 mL) was degassed by vacuum purging thenbubbling argon through the mixture (×3). To the dark red mixture wasadded 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide (7.57g, 21.8 mmol) as a solution in DMA (20.5 mL) and the mixture was heatedat 85° C. for 1.75 hours. During the reaction the mixture turned green,then brown. The reaction mixture was diluted with EtOAc and an aqueoussaturated ammonium chloride solution. Water was added to dissolve mostof the solids and the mixture was filtered through Celite®. The organicphase of the filtrate was separated and the aqueous phase extracted withEtOAc (×2). The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated in vacuo. The resultant residue was purifiedby flash chromatography (SiO₂, 5-40% EtOAc in cyclohexane) to give thetitle compound as a pink solid (4.96 g, 73%). LCMS: R_(T)=5.13 min,[M+H]⁺=468

Example 24 4-Piperidine-1-carboxylic acid tert-butyl ester zinc iodide

The title compound was prepared by a similar procedure to3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide using4-iodo-piperidine-1-carboxylic acid tert-butyl ester instead of3-iodo-azetidine-1-carboxylic acid tert-butyl ester.

Example 254-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared by a similar procedure to3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester using 4-piperidine-1-carboxylic acid tert-butylester zinc iodide instead of 3-azetidine-1-carboxylic acid tert-butylester zinc iodide. The title compound was isolated as a brown solid (480mg, 76%). LCMS: R_(T)=5.24 min, [M+H]⁺=496

Example 26 3-Pyrrolidine-1-carboxylic acid tert-butyl ester zinc iodide

The title compound was prepared by a similar procedure to3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide using3-iodo-pyrrolidine-1-carboxylic acid tert-butyl ester instead of3-iodo-azetidine-1-carboxylic acid tert-butyl ester.

Example 273-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared by a similar procedure to3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester using 3-pyrrolidine-1-carboxylic acid tert-butylester zinc iodide instead of 3-azetidine-1-carboxylic acid tert-butylester zinc iodide. The title compound was isolated as a red-brown gummysolid (22 mg, 6%). LCMS: R_(T)=5.20 min, [M+H]⁺=482

Example 284-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared by a similar procedure to3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester using9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 instead of8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 and 4-piperidine-1-carboxylic acid tert-butyl ester zinc iodideinstead of 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide.LCMS: R_(T)=5.12 min, [M+H]⁺=496

Example 292-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt

The title compound was prepared by a similar procedure to8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 using4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-piperidine-1-carboxylicacid tert-butyl ester instead of3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester. The title compound was isolated as a beige solid(1.75 g, 93%). LCMS: R_(T)=3.28 min, [M+H]⁺=396

Example 308-[1-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

The title compound was prepared by a similar procedure to8-(1-isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneusing (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde instead ofacetone and adding 1.0 eq. diisopropylethylamine to the reactionmixture. The product was isolated as a colourless oil (127 mg, 32%).LCMS: R_(T)=3.37 min, [M+H]⁺=482

Example 31(1-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamicacid tert-butyl ester

The title compound was prepared by a similar procedure to(R)-2-hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-oneusing 1-(Boc-amino)cyclopropane carboxylic acid and DMF to give(1-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamicacid tert-butyl ester isolated as a white solid (228 mg, 66%). LCMS:R_(T)=4.72 min, [M+H]⁺=551

Example 322-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionicacid methyl ester

The title compound was prepared by a similar procedure to2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamideusing methyl 2-bromoisobutyrate, cesium carbonate instead of potassiumcarbonate and DMF. The reaction was performed at 80° C. to give2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionicacid methyl ester isolated as a white solid (147 mg, 60%). LCMS:R_(T)=3.16 min, [M+H]⁺=468

Example 338-(1-Ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a mixture of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (100 mg, 0.2 mmol) in dry DCM (2 mL) was addedtriethylamine (60 μL, 0.4 mmol) and the reaction mixture was stirred for1 hour. The mixture was washed with water followed by brine, dried(Na₂SO₄) and then treated with triethylamine (30 μL, 0.2 mmol) followedby 2-chloroethane-sulfonyl chloride (42 μL, 0.4 mmol) in dry DCM (1 mL).The reaction mixture was stirred at RT for 18 hours then diluted withDCM and washed with water followed by brine, dried (Na₂SO₄) andconcentrated in vacuo to give8-(1-Ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneas a light brown oil (75 mg, 82%). ¹H NMR δ (ppm) (CDCl₃): 8.39 (1H, d,J=8.22 Hz), 7.93 (1H, s), 7.16 (1H, dd, J=8.22, 1.98 Hz), 7.02 (1H, d,J=1.91 Hz), 6.61 (1H, dd, J=16.50, 9.95 Hz), 6.39 (1H, d, J=16.66 Hz),6.18 (1H, d, J=9.95 Hz), 5.93-5.87 (1H, m), 4.45-4.39 (2H, m), 4.28-4.22(2H, m), 4.07-3.97 (2H, m), 3.81 (1H, t, J=7.81 Hz), 3.46-3.40 (2H, m),1.64 (6H, d, J=6.65 Hz)

Example 348-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid

A mixture of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidethyl ester (3.32 g, 9.38 mmol), MeOH (75 mL) and water (50 mL) wastreated with sodium hydroxide (562 mg, 14.06 mmol) at RT. After 90minutes THF (20 mL) was added to aid dissolution. After 60 minutes themixture was concentrated in vacuo, dissolved in water (200 mL) andcarefully acidified to pH1 with 2N HCl. The resulting solid wascollected by filtration, washed with water and dried under vacuum toafford8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(1.86 g, 61%). LCMS R_(T)=4.91 min, no [M+H]⁺=326/328

Example 35[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamicacid benzyl ester

To a suspension of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(1.86 g, 5.70 mmol) in anhydrous THF (75 mL) was addeddiisopropylethylamine (2 mL, 11.4 mmol), HATU (2.39 g, 6.27 mmol) and1-benzyloxycarbonyl-2-methyl-isothiourea (1.47 g, 6.56 mmol) at RT.After stirring for 24 hours an aqueous saturated sodium bicarbonatesolution was added and the mixture extracted with 1:1 EtOAc/THF solution(×2). The organic layers were combined, washed with brine, dried(Na₂SO₄) and concentrated in vacuo. The resulting solid was added to DMF(50 mL) and treated with diisopropylethylamine (4 mL, 22.8 mmol) andisopropylhydrazine hydrochloride (941 mg, 8.55 mmol). The mixture washeated to 95° C. and scrubbed with 1N NaOH solution and NaOCl solution.After 2 hours the mixture was allowed to cool to RT, extracted withEtOAc and washed with water. The organic layer was dried (Na₂SO₄) andconcentrated in vacuo. The resultant residue was purified by flashchromatography (SiO₂, gradient 0-50% EtOAc in cyclohexane) to afford[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamicacid benzyl ester (1.75 g, 57%). LCMS: R_(T)=5.11 min, [M+H]⁺=540/542

Example 363-[2-(5-Benzyloxycarbonylamino-2-isopropyl-2H-[1,2,4]-triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester

Following a similar procedure to3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester using[5-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamicacid benzyl ester,3-[2-(5-Benzyloxycarbonylamino-2-isopropyl-2H-[1,2,4]-triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester was prepared (394 mg, 36%). LCMS: R_(T)=4.98 min,[M+H]⁺=617

Example 37[5-(8-azetidin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamicacid benzyl ester hydrochloride salt

To a solution of3-[2-(5-benzyloxycarbonylamino-2-isopropyl-2H-[1,2,4]-triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester (504 mg, 0.82 mmol) in DCM (10 mL) was added 4NHCl in dioxan (2 mL) at RT. After stirring for 2 hours MeOH (2 mL) and4N HCl in dioxan (3 mL) were added to the mixture. After stirring for 60minutes the reaction mixture was concentrated in vacuo. The resultingsolid was treated with ether, collected by filtration and dried undervacuum to afford[5-(8-azetidin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamicacid benzyl ester hydrochloride salt (379 mg, 84%). LCMS: R_(T)=3.04min, [M+H]⁺=517

Example 38(1-Isopropyl-5-{8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H-[1,2,4]triazol-3-yl)-carbamicacid benzyl ester

The title compound was prepared by a similar procedure to2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneusing8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene235 HCl salt and diisopropylethylamine. The reaction mixture was dilutedwith DCM and water. The organic phase dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash chromatography (SiO₂, 0-4% MeOHin DCM) to give(1-Isopropyl-5-{8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H-[1,2,4]triazol-3-yl)-carbamicacid benzyl ester (157 mg, 73%). LCMS: R_(T)=3.04 min, [M+H]⁺=623

Example 39(2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamicacid tert-butyl ester

Following a similar method toN-(2-hydroxy-2-methyl-propyl)-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamideusing Boc-Aib-OH,(2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamicacid tert-butyl ester was isolated as a colourless oil (203 mg, 59%).LCMS: R_(T)=4.77 min, [M+H]⁺=553

Example 40{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-aceticacid tert-butyl ester

Following a similar procedure to2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamideusing tert-butyl bromoacetate,{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-aceticacid tert-butyl ester was isolated as a colourless oil (97 mg, 33%).LCMS: R_(T)=3.63 min, [M+H]⁺=482

Example 41{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-aceticacid TFA salt

Following a similar procedure to8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 using{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-aceticacid tert-butyl ester and TFA:DCM (1:2),{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-aceticacid TFA salt was isolated as a white solid (75 mg, 90%). ¹H NMR δ (ppm)(DMSO-d6): 8.35 (1H, d, J=8.20 Hz), 8.11 (1H, d, J=0.75 Hz), 7.29 (1H,d, J=8.33 Hz), 7.21 (1H, s), 5.85-5.77 (1H, m), 4.48-4.39 (2H, m),4.41-4.35 (2H, m), 4.36-4.22 (3H, m), 3.48-3.42 (2H, m), 1.55 (6H, d,J=6.59 Hz) plus 2 protons obscured by the water peak and 2 exchangeableprotons not observed.

Example 422-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol

To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg,2.58 mmol) in 2,2-dimethyl-oxirane (3 mL) was added cesium carbonate(130 mg, 0.40 mmol). The reaction was heated at 120° C. for 30 minutesusing microwave irradiation. The reaction was cooled then filteredthrough a plug of cotton wool, flushing with DCM. The filtrate wasconcentrated in vacuo giving2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olas a beige solid (620 mg, 90%). ¹H NMR δ (ppm) (CDCl₃): 7.82 (1H, d,J=0.65 Hz), 7.69 (1H, s), 4.07 (2H, s), 1.32 (12H, s), 1.15 (6H, s). 1Exchangeable proton not observed

Example 438-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine

To a solution of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(12.5 g, 38.3 mmol) in tert-butanol (250 mL) were added triethylamine(5.5 mL, 40 mmol) and diphenylphosphoryl-azide (8.6 mL, 40 mmol). Thereaction mixture was stirred at 95° C. for 16 hours, then allowed tocool down to RT, and concentrated in vacuo. The resultant residue wasdissolved in EtOAc, washed successively with water, aqueous saturatedsodium bicarbonate solution followed by brine, dried (MgSO₄) andconcentrated in vacuo. The resultant residue was dissolved in DCM (150mL) and treated with TFA (50 mL). The reaction mixture was stirred at RTfor 3 hours then concentrated in vacuo. The resulting residue wastriturated with 20% EtOAc/cyclohexane and filtered to afford8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine as anoff-white solid (7.94 g, 70%). LCMS: R_(T)=3.13 min, [M+H]⁺=297/299

Example 44 2,8-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a solution of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine (1.69 g,5.68 mmol) in MeCN (60 mL) was added CuBr₂ (2.54 g, 11.36 mmol). Thereaction was purged with argon and cooled to 0° C. before the dropwiseaddition of 2-methyl-2-nitrosooxy-propane (1.35 mL, 11.36 mL). Thereaction was warmed to RT and stirred for 20 hours, then quenched withan aqueous saturated sodium bicarbonate solution (30 mL) and extractedwith DCM (3×50 mL). The combined organic phases were washed with brine(30 mL), dried (Na₂SO₄) and concentrated in vacuo. The residue wassubjected to flash chromatography (SiO₂, 0-10% DCM in cyclohexane) togive 2,8-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as awhite solid (1.45 g, 70%). LCMS: R_(T)=4.54 min, [M+H]⁺=360/362/364.

Example 45 Mixture of4-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneand4-(8-Iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one(˜1:1)

A microwave vial was charged with2,8-dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (429 mg, 1.2mmol), 2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one (188 mg, 1.7 mmol),trans-1,2-dimethylamino-cyclohexane (187 μL, 1.2 mmol), copper (I)iodide (227 mg, 1.2 mmol), cesium carbonate (540 mg, 1.7 mmol) and1,4-dioxan (20 mL) and sealed. The vial was evacuated and purged withargon (×3) then the reaction mixture was heated at 100° C. for 18 h. Themixture was concentrated in vacuo and the residue purified by flashchromatography (SiO₂, 0-10% EtOAc in DCM) to give the mixture of4-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneand4-(8-Iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one(˜1:1) as an off-white solid (41 mg). LCMS: R_(T)=4.39, 4.44 min,[M+H]⁺=393/395 and 441

Example 46 2-Isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one

To a solution of [1-ethoxy-eth-(Z)-ylidene]-carbamic acid ethyl ester(834 mg, 5.24 mmol) in toluene (15 mL) was added isopropyl hydrazinehydrochloride (637 mg, 5.76 mmol) followed by triethylamine (803 μL,5.76 mmol). The reaction vessel was sealed and stirred at 45° C. for 45minutes before the addition of triethylamine (803 μL, 5.76 mmol). Theresultant mixture was heated to 90° C. and stirred for 17 hours, thencooled and concentrated in vacuo. The resultant residue was purified byflash chromatography (SiO₂, gradient 0% to 8% 2M NH₃/MeOH in DCM) togive 2-Isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one as an offwhite solid (329 mg, 44%). LCMS: R_(T)=2.16 min, [M+Na]⁺=164

Example 47 Mixture of4-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-oneand4-(8-Iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one(˜1:1)

Following a similar procedure for the mixture of4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneand4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneusing 2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one, the mixtureof4-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-oneand4-(8-Iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one(˜1:1) was isolated as an off-white solid (49 mg). LCMS: R_(T)=5.17 min,[M+H]⁺=421/423 and 469

Example 484-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-5-isopropyl-2-methyl-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was prepared by a similar method to the mixture of4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneand4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneusing 5-isopropyl-2-methyl-2,4-dihydro-[1,2,4]triazol-3-one andpotassium carbonate.4-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-5-isopropyl-2-methyl-2,4-dihydro-[1,2,4]triazol-3-onewas isolated as a yellow solid (11 mg, 17%). LCMS: R_(T)=5.19 min,[M+H]⁺=421/423

Example 495-Isopropyl-2-methyl-4-(8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one

The title compound was prepared by a similar procedure to4-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneusing1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole.5-Isopropyl-2-methyl-4-(8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,4-dihydro-[1,2,4]triazol-3-onewas isolated as a white solid (9 mg, 65%). LCMS: R_(T)=4.84 min,[M+H]⁺=537

Example 50 1-Ethenesulfonyl-3,3-difluoro-azetidine

The title compound was prepared by a similar procedure to8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneusing 3,3-difluoroazetidine hydrochloride salt.1-Ethenesulfonyl-3,3-difluoro-azetidine was isolated as a light brownoil after flash chromatography (SiO₂, DCM) (171 mg, 61%). ¹H NMR δ (ppm)(CDCl₃): 6.56 (1H, dd, J=16.56, 9.83 Hz), 6.40 (1H, d, J=16.59 Hz), 6.20(1H, d, J=9.83 Hz), 4.32-4.17 (4H, m)

Example 518-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a solution of8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 (10.76 g, 0.03308 mol) in toluene (200 mL) was addedmethanamine, 1,1-Dimethoxy-N,N-dimethyl-(19.683 g, 0.1640 moles). Thereaction was heated to 95° C. for 3 hours. The toluene was removed invacuo to give a beige powder. The crude (12.58 g, 0.03308 mol) wasredissolved in acetic acid (120 mL) and trifluoroethyl hydrazine (6.269mL, 0.04962 mol) was added. The reaction was heated to 95° C. for 4 h.The AcOH was removed in vacuo. The product was loaded as a solid ontosilica and purified by flash chromatography (5-70% EtOAc in hexanes).The appropriate fractions were combined and concentrated to give8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(6.176 g) as an off-white solid. MS(ESI+) 431.0/433.0.

Example 528-Bromo-2-[2-(2,2,2-trifluoro-1-methyl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Following the procedure for8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 was reacted with (2,2,2-Trifluoro-1-methyl-ethyl)-hydrazine togive8-Bromo-2-[2-(2,2,2-trifluoro-1-methyl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.MS(ESI+) 445.0/447.0.

Example 538-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Following the procedure for8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 was reacted with pyridin-4-ylmethyl-hydrazine to give8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.

Example 548-Bromo-2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Following the procedure for8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 was reacted with Pyridin-2-ylmethyl-hydrazine to give8-Bromo-2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.MS(ESI+) 440.0/442.0.

Example 558-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Following the procedure for8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 was reacted with (1-methyl-piperidin-4-yl)-hydrazine to give8-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.

Example 562-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-ethanol

Following the procedure for8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 was reacted with 2-hydrazino-ethanol to give2-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-ethanol.MS(ESI+) 393.0/395.0.

Example 571-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-ol

Following the procedure for8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 was reacted with 1-hydrazino-propan-2-ol to give1-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-ol.MS(ESI+) 407.0/409.0.

Example 58 Acetic acid2-[5-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propylester

Following the procedure for8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 was reacted with 1-hydrazino-propan-1-ol to give Acetic acid2-[5-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propylester. MS(ESI+) 449.0/451.0.

Example 598-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Following the procedure for8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide 25 was reacted with (2-morpholin-4-yl-ethyl)-hydrazine to give8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.MS(ESI+) 462.1/464.1.

Example 602-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile

8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (0.32 g, 0.6 mmol) was suspended in water (2.5 mL) andtreated with sodium cyanide (50 mg, 0.6 mmol). A solution of acetone (60mg, 0.9 mmol) in water (0.25 mL) was added followed by THF (˜2 mL) toaid dissolution. The reaction mixture was stirred at RT for 18 hoursthen extracted with DCM (×2). The combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo to afford2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile(0.26 g, quant.) LCMS: R_(T)=4.66 min, [M+H]⁺=435

Example 612-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile

The title compound was prepared by a similar procedure to2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrileusing2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt to give2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrileisolated as an orange oil (346 mg) as a roughly 1:1 mixture with2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand was used without further purification. LCMS: R_(T)=4.71 min,[M+H]⁺=463

Example 62 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile

A solution of 8-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene (0.500grams, 1.77 mmol) and copper cyanide (0.48 grams, 5.30 mmol) in 10 ml ofDMF was flash heated on Biotage microwave. The reaction mixture wasdiluted with a large volume of EtOAc and this solution was filteredthrough celite by vacuum filtration. The filtrate was plated onto a 1/1mixture on silica/celite and dry load purified by MPLC on a 14 gramsilica column eluting with 10 to 80% EtOAc/heptanes to give 500 mg(123%) of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile asdetermined by LC/MS.

Example 632-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile

A solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile(240 mg, 1.05 mmol) in 3 ml of DMF was treated with NBS (206 mg, 1.16mmol) at room temperature for 15 hours. The reaction mixture was dilutedwith a large volume of EtOAc and the organic was washed with water andsaline and concentrated in vacuo to a solid. This residue was filteredonto celite and purified by MPLC on a 14 gram silica column, elutingwith 20-80% EtOAc/heptanes to give 200 mg (62%) of2-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile as awhite powder in high purity as determined by LC/MS.

Example 642-(2-methylpyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile

A 2 ml microwave vial was loaded with a slurry of2-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carbonitrile (170 mg,0.55 mmol) and pyridine-2-amino boronic acid pinacolester (130 mg, 0.61mmol) in 0.800 ml of aqueous 2M Sodium carbonate and 1.2 ml of ACN. Thereaction mixture was degassed by bubbling nitrogen through the solutionfor several minutes. Next palladium tetrakis (51 mg, 2 mmol) was addedto the reaction mixture and the vial was tightly capped and flash heateda Biotage microwave at 180 C for 10 minutes. The cooled reaction mixturewas diluted with a large volume of EtOAc and the organic was washed withwater and saline and concentrated in vacuo. The resulting residue wastaken into DMF and purified by preparative RP-HPLC to give 32 mg (17%)of2-(2-methylpyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile

Example 659-Chloro-2-[5-(2,4-difluoro-phenyl)-3H-imidazol-4-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene

To a solution of1-(9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-2-yl)-2-(2,4-difluoro-phenyl)-ethane-1,2-dione(200 mg, 0.483 mmol) in 1.2 ml of acetic acid was added paraformaldehyde(14.8 mg, 0.493 mmol) and ammonium acetate (380 mg, 4.83 mmol). Thereaction mixture was flash heated on a Biotage microwave. The cooledreaction mixture was dilute with EtOAc and washed with saline and theorganics was concentrated in vacuo to solid. The crude was purified byMPLC on a 14 gram silica column eluting with 10-70% EtOAc/heptanes togive9-chloro-2-[5-(2,4-difluoro-phenyl)-3H-imidazol-4-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(150 mg, 73%) as a yellow powder.

Example 101((R)-2-Hydroxymethyl-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone101

To an ice water cooled slurry of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(1.0 g, 0.003 mol) in methylene chloride (0.5 mL) was added two drops ofanhydrous DMF followed by the drop-wise addition of oxalyl chloride (0.5mL, 0.006 mol). The mixture was stirred for 1 hour, concentrated invacuo and the corresponding acid chloride,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonylchloride, was used without purification.

To a solution of D-(−)-Prolinol (0.205 g, 2.03 mmol) inN,N-Diisopropylamine (0.758 mL, 4.35 mmol) and N,N-Dimethylformamide(4.49 mL, 58.0 mmol) at room temperature was added8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonylchloride (0.500 g, 1.45 mmol) portionwise. The reaction mixture wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith ethyl acetate, washed with brine, and concentrated in vacuo to give(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanonewhich was not further purified.

(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone(0.297 g, 0.726 mmol),4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (0.211 g,1.09 mmol), 2 M Sodium bicarbonate in water (1 mL, 2.0 mmol) andacetonitrile (2 mL, 40 mmol) were combined in a microwave vial andthoroughly purged with nitrogen. AddedTetrakis(triphenylphosphine)palladium(0) (0.0838 g, 0.0726 mmol) andheated on the Emrys microwave at 150° C. for 10 minutes. Cooled to roomtemperature, diluted with ethyl acetate, washed with brine andconcentrated the organic layer in vacuo. Purified by HPLC to give 101(48 mg, 17% yield, M+1 397.1)

Example 1028-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid isopropyl-methyl-amide 102

To a solution of N-methylpropan-2-amine (0.265 g, 3.63 mmol) inN,N-Diisopropylamine (0.758 mL, 4.35 mmol) and N,N-Dimethylformamide(4.49 mL, 58.0 mmol) at room temperature was added8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonylchloride (0.500 g, 1.45 mmol) portionwise. The reaction mixture wasstirred at room temperature for 1 hour, diluted with ethyl acetate,washed with brine, and concentrated in vacuo to give8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidisopropyl-methyl-amide which was not further purified.

8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidisopropyl-methyl-amide (0.292 g, 0.766 mmol),4,4,5,5-Tetramethyl-2-(1H-pyrozol-4-yl)-1,3,2-dioxaborolane (0.208 g,1.07 mmol), 2 M Sodium bicarbonate in water (1 mL, 2.0 mmol) andacetonitrile (2 mL, 40 mmol) were combined ion a microwave vial andthoroughly purged with nitrogen. AddedTetrakis(triphenylphosphine)palladium(0) (0.0824 g, 0.0714 mmol) andheated on the Emrys microwave at 150° C. for 10 minutes. Cooled to roomtemperature, diluted with ethyl acetate, washed with brine andconcentrated the organic layer in vacuo. Purified by HPLC to give 102(50 mg, 18% yield, M+1 369.0)

Example 1038-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 103

To a degassed solution of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(1.40 g, 4.29 mmol),4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (1.0 g, 5.0mmol), 2 M Sodium bicarbonate in water (6.0 mL, 10.0 mmol) andacetonitrile (8.0 mL, 200 mmol) in a microwave vial was addedTetrakis(triphenylphosphine)palladium(0) (0.499 g, 0.432 mmol). The vialwas heated on the Emrys microwave at 150° C. for 20 minutes. Cooled toroom temperature and diluted with ethyl acetate, the precipitate wasfiltered off, washed with ethyl acetate and water and dried under vacuumto give8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (1.4 g, 103% yield).

To a solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (363.8 mg, 1.161 mmol) in N,N-dimethylformamide (39-60 equiv.) andN,N-Diisopropylamine (1.5 equiv.) was added 2-(isopropylamino)ethanol(133.1 mg, 1.29 mmol) followed by the addition ofN,N,N′N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uraniumhexafluorophosphate (1.1 equiv.). The reaction mixture was heated at 50°C. for 2 hrs to 24 hours depending on when complete by LCMS. Reactionmixture was concentrated on the genevac and purified by HPLC or dilutedwith ethyl acetate, washed with brine, dried over sodium sulfate andconcentrated in vacuo prior to purification by HPLC to give 103 (70 mg,15% yield, M+1 399.1)

Example 1042-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid (2-methoxy-ethyl)-amide 104

Similar to as described in General procedure F,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 was reacted with 2-methoxyethylamine to give 104 after purificationby reverse phase HPLC (368 mg). LCMS: 414.1

Example 1052-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol105

Similarly to as described in General Procedure C,8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 was reacted with ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetateto give{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-aceticacid ethyl ester as a colorless solid. LCMS: 466.

A solution of{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-aceticacid ethyl ester in THF (200 mL) was cooled to 0° C. and treateddropwise with a solution of 1M LiAlH₄ (in THF, 23 mL, 23 mmol, 2.5 eq).After 1 h, LCMS indicated consumption of starting material. A solutionof saturated sodium sulfate was added slowly until H₂ evolution ceased.˜30 g of solid magnesium sulfate was added and the whole was stirred for20 min. Filtration over celite (EtOAc and DCM) followed by concentrationof the filtrant gave a crude residue that was purified by reverse-phaseHPLC to give 1.4 g of 105 (43%). LCMS: 423.1. ¹H NMR (400 MHz, DMSO) δ8.32 (d, J=8.3 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.43(dd, J=8.3, 1.6 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 5.84 (dt, J=13.2, 6.6Hz, 1H), 4.91 (t, J=5.3 Hz, 1H), 4.39 (t, J=4.9 Hz, 2H), 4.16 (t, J=5.6Hz, 2H), 3.77 (q, J=5.5 Hz, 2H), 3.44 (t, J=4.9 Hz, 2H), 1.56 (d, J=6.6Hz, 6H).

Alternatively, following the procedure for 376,2-(1-isopropyl-1H-imidazol-2-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand MeOH as the solvent gave 105 as a solid (134 mg). LCMS: R_(T)=10.20min, [M+H]⁺=422. ¹H NMR δ (ppm) (DMSO-d6): 8.25 (1H, d, J=8.27 Hz), 8.17(1H, s), 7.90 (1H, d, J=0.76 Hz), 7.81 (1H, s), 7.39-7.35 (2H, m), 7.24(1H, d, J=1.82 Hz), 5.66-5.56 (1H, m), 4.33 (2H, t, J=5.05 Hz), 4.11(2H, t, J=5.77 Hz), 3.72 (2H, t, J=5.66 Hz), 3.41-3.32 (2H, m), 1.51(6H, d, J=6.67 Hz). 1 Exchangeable proton not observed

Example 106 1H-Pyrazole-4-carboxylic acid{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl}-amide106

To a solution of{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-methylaminein tetrahydrofuran was added diisopropylethylamine followed by1H-pyrazole-4-carboxylic acid andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate. The reaction was stirred at room temperature forabout 3 hours. The mixture was partitioned between saturated sodiumbicarbonate and ethyl acetate and extracted 3 times with ethyl acetate.The organic layers were combined, dried with MgSO₄, and concentrated.The crude was purified by reverse-phase HPLC to give was reacted with togive 106. MS(ESI+) 476.1. ¹H NMR (400 MHz, DMSO) δ 13.03 (br, 1H), 8.60(m, 1H), 8.32-8.22 (m, 2H), 8.07 (s, 2H), 7.15 (dd, J=16.3, 8.3, 1H),7.00 (s, 1H), 5.84 (q, J=8.7, 2H), 4.43 (d, J=5.9, 2H), 4.36 (t, J=4.9,2H), 3.45 (t, J=4.9, 2H)

Example 1072-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid ((S)-2-hydroxy-propyl)-amide 107

To a solution of (S)-1-Amino-propan-2-ol in degassed toluene (2.32 mL)under nitrogen atmosphere was added8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,Pd(OAc)2, 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene and sodiumcarbonate. The mixture was purged with carbon monoxide and heated to 90°C. under a carbon monoxide balloon for 24 hours. The reaction wasdiluted with ethyl acetate, filtered through celite, and purified byreverse-phase HPLC to give 107. MS(ESI+) 454.0

Example 1082-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide 108

Similar to as described in General procedure F,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 was reacted with 3-(2-aminoethoxyl)propan-1-ol to give 108 afterpurification by reverse phase HPLC (140 mg). LCMS: 444.1.

Example 109{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-[2-(1,1-dioxo-1S-thiomorpholin-4-yl)-ethyl]-amine109

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol), 2-(1,1-Dioxo-116-thiomorpholin-4-yl)-ethylamine (210mg, 1.2 mmol), Pd(OAc)₂ (23 mg, 0.10 mmol), Xphos (47 mg, 0.10 mmol),t-BuONa (230 mg, 2.0 mmol) and dioxane (4 mL) were added in a 10 mL ofsealed tube, and the mixture was heated by microwave at 112° C. for 7min under N₂. The reaction mixture was filtered to gather the solutionand water was added. The mixture was extracted by DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, concentrated in vacuo,and purified by preparative HPLC to 109 (47 mg, yield: 8.4%). ¹HNMR(DMSO-d₆, 400 MHz): δ8.25 (s, 1H), 7.91-7.85 (m, 1H), 7.72 (t, J=10 Hz,1H), 7.42 (t, J=0.8 Hz, 1H), 7.07-7.03 (m, 2H), 6.40 (d, J=4.8 Hz, 1H),4.13 (t, J=4.4 Hz, 2H), 3.52-3.34 (m, 2H), 3.28-3.11 (m, 6H), 3.01-3.96(m, 6H). ESI-MS: m/z=559 [M+H⁺]

Example 1102-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(4-methyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene110

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (49 mg, 0.3 mmol), morpholine (130 mg,1.44 mmol),2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 120° C. for 1 h under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford115 mg of 110 (yield=31%). ¹H NMR (CDCl₃, 400 MHz): δ8.12-8.10 (m, 1H),7.58-7.52 (m, 1H), 7.15-7.05 (m, 4H), 6.55 (d, J=9.2 Hz, 1H), 4.25-4.23(m, 2H), 3.75-3.63 (m, 5H), 3.12-3.10 (m, 2H), 2.93-2.91 (m, 4H),2.62-2.57 (m, 3H). LC-MS (ESI): m/z=480 [M+H]⁺

Example 1112-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carboxylicacid (2-hydroxy-ethyl)-amide 111

9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 (0.350 g, 0.894 mmol), ethanolamine (0.162 mL, 2.68mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.054 g, 0.093mmol), and sodium carbonate (0.569 g, 5.37 mmol) were added to anitrogen flushed flask. To the mixture was added toluene (20 mL) andnitrogen was bubbled through the reaction mixture for 2 minutes. To thereaction mixture was added Pd(OAc)₂ (0.021 g, 0.093 mmol), then CO wasbubbled through the reaction mixture for 1 minute and the reaction wasplaced under a CO balloon and stirred and heated at 85° C. for 18 hours.LCMS showed very little conversion from starting material to product. Tothe reaction mixture was added ethanolamine (0.162 mL, 2.68 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.054 g, 0.093 mmol),sodium carbonate (0.569 g, 5.37 mmol), and Pd(OAc)₂ (0.021 g, 0.093mmol), then CO was bubbled through the reaction mixture for 1 minute andthe reaction was placed under a CO balloon and stirred and heated at 85°C. for 18 hours. The reaction mixture was cooled to room temperature,diluted with EtOAc, and filtered through a pad of celite. The filtratewas concentrated under reduced pressure and diluted with EtOAc. Thesolution was washed sequentially with water, and brine, before dryingover MgSO₄ and concentrating under reduced pressure. The crude materialwas dissolved in DMF and purified by reverse phase HPLC provide 111 (3mg, 8%). ¹H NMR (400 MHz, DMSO) δ 8.92 (d, J=2.1, 1H), 8.37 (t, J=5.5,1H), 8.08 (d, J=21.9, 1H), 7.75 (dd, J=8.4, 2.1, 1H), 7.12 (d, J=8.4,1H), 5.83 (dt, J=13.0, 6.6, 1H), 4.70 (t, J=5.4, 1H), 4.42 (t, J=4.8,2H), 3.56-3.44 (m, 4H), 3.38-3.33 (m, 2H), 1.57 (d, J=6.6, 6H). MS(ESI(+)): m/z 400.1 (M+H)

Example 1122-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid (2-hydroxy-ethyl)-amide 112

Following the procedure for 107,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with ethanolamine to give 112. MS(ESI+) 440.0. ¹H NMR (400MHz, DMSO) δ 8.47 (t, J=5.4, 1H), 8.37 (d, J=8.3, 1H), 8.30 (s, 1H),7.68 (dd, J=8.3, 1.4, 1H), 7.57 (d, J=1.3, 1H), 5.85 (q, J=8.7, 2H),4.71 (br, 1H), 4.41 (t, J=4.9, 2H), 3.58-3.44 (m, 4H), 3.36-3.30 (m,2H).

Example 1132-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid (2,2-difluoro-ethyl)-amide 113

Following the procedure for 107,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with 2,2-difluoro-ethylamine to give 113. MS(ESI+) 460.0. ¹HNMR (400 MHz, DMSO) δ 8.90 (t, J=5.8, 1H), 8.40 (d, J=8.3, 1H), 8.30 (s,1H), 7.71 (dd, J=8.3, 1.6, 1H), 7.60 (d, J=1.5, 1H), 6.12 (tt, J=55.9,3.9, 1H), 5.86 (q, J=8.8, 2H), 4.42 (t, J=4.9, 2H), 3.77-3.58 (m, 2H),3.51 (t, J=4.9, 2H)

Example 1148-[1-(2-Morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene114

To a microwave vial was added8-bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand potassium acetate in acetonitrile and water. The solution wasthoroughly purged and degassed with nitrogen for 5 minutes.4-{2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-morpholineand Tetrakis(triphenylphosphine)palladium were added the vial was sealedimmediately. The reaction was heated in the microwave for about 20minutes at 140° C.

The mixture was diluted with methylene chloride and filtered throughcelite. Saturated NH₄Cl was added and the mixture was extracted 3 timeswith methylene chloride. The organic layers were combined, dried withMgSO₄ and concentrated. The crude was purified by reverse-phase HPLC togive 114. MS(ESI+) 532.2. ¹H NMR (400 MHz, DMSO) δ 8.30-8.25 (m, 3H),7.96 (s, 1H), 7.43 (dd, J=8.3, 1.6, 1H), 7.30 (d, J=1.5, 1H), 5.86 (q,J=8.7, 2H), 4.40 (t, J=4.9, 2H), 4.24 (t, J=6.5, 2H), 3.61-3.51 (m, 4H),3.47 (t, J=4.9, 2H), 2.75 (t, J=6.5, 2H), 2.46-2.35 (m, 4H)

Example 1159-[1-(2-Morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene115

8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholinewere reacted under palladium Suzuki conditions to give 115 (17% yield).LC/MS (ESI+): m/z 532 (M+H). ¹H NMR (400 MHz, DMSO) δ 8.48 (d, J=2.1,OH), 8.30 (s, OH), 8.07 (s, OH), 7.76 (s, OH), 7.49 (dd, J=8.3, 2.2,OH), 7.09 (d, J=8.3, OH), 5.89 (q, J=8.6, OH), 4.38 (t, J=4.9, OH), 4.25(t, J=6.6, OH), 3.61-3.51 (m, 1H), 3.48 (t, J=4.9, OH), 2.75 (t, J=6.6,OH), 2.45-2.35 (m, 1H)

Example 116(2-Morpholin-4-yl-ethyl)-(5-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyridin-2-yl)-amine116

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with(2-Morpholin-4-yl-ethyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amineto give 116. MS(ESI+) 558.2. ¹H NMR (400 MHz, DMSO) δ 8.41 (d, J=2.1,1H), 8.32 (d, J=8.4, 1H), 8.29 (s, 1H), 7.79 (dd, J=8.8, 2.4, 1H), 7.45(dd, J=8.4, 1.7, 1H), 7.30 (d, J=1.6, 1H), 6.59 (dd, J=10.9, 7.1, 2H),5.87 (q, J=8.7, 2H), 4.41 (t, J=4.9, 2H), 3.64-3.54 (m, 4H), 3.47 (t,J=4.9, 2H), 3.42 (dd, J=12.5, 6.4, 2H), 2.50-2.47, (m, 2H), 2.40-2.44(m, 4H)

Example 117{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(1-methyl-pyrrolidin-3-ylmethyl)-amine117

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (49 mg, 0.3 mmol),C-(1-Methyl-pyrrolidin-3-yl)-methylamine (164 mg, 1.44 mmol),2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol) tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 120° C. for 1 h under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford120 mg of 117 (yield=34%). ¹H NMR (CDCl₃, 400 MHz): δ8.67-8.52 (m, 1H),8.11-8.06 (m, 1H), 7.58-7.50 (m, 1H), 7.16-7.02 (m, 3H), 6.96-6.90 (m,1H), 6.42-6.31 (m, 1H), 4.28-4.21 (m, 2H), 3.50-2.84 (m, 8H), 2.72-2.64(m, 3H), 2.38-2.22 (m, 1H), 1.94-1.82 (m, 1H). LC-MS (ESI): m/z=495[M+H]⁺

Example 118{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(1-methyl-piperidin-4-ylmethyl)-amine118

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (49 mg, 0.3 mmol),C-(1-Methyl-piperidin-4-yl)-methylamine (184 mg, 1.44 mmol),2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 120° C. for 1 h under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford135 mg of 118 (yield=37%). ¹H NMR (CDCl₃, 400 MHz) δ: 8.49 (s, 1H), 8.01(s, 1H), 7.48-7.45 (m, 1H), 7.08-6.98 (m, 3H), 6.88 (s, 1H), 6.24-6.00(m, 1H), 4.16-4.12 (m, 2H), 3.42-2.84 (m, 4H), 3.02-2.96 (m, 2H), 2.55(s, 3H), 2.38-2.32 (m, 2H), 1.82-1.80 (m, 1H), 1.76-1.70 (m, 2H),1.68-1.59 (m, 2H). LC-MS (ESI): m/z=509 [M+H]⁺

Example 119[2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-(2,2,2-trifluoro-ethyl)-amine119

To a solution of2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde(180 mg, 0.53 mmol) in DCE (7 mL+5% AcOH) was added trifluoroethylamine(46 μL, 0.58 mmol) and the mixture was stirred for 30 minutes. Sodiumtriacetoxyborohydride (134 mg, 0.64 mmol) was added and the solution wasstirred under nitrogen for 65 hours. The reaction mixture was dilutedwith aqueous saturated sodium bicarbonate solution and DCM and thephases were separated. The organic layer was washed with brine, dried(Na₂SO₄) and concentrated in vacuo. The resultant residue was purifiedby flash chromatography (SiO₂, 0-5% 2M NH₃/MeOH in DCM) to give acolourless oil. The oil was triturated with ether/cyclohexane to give119 as a grey solid (138 mg, 61%). LCMS: R_(T)=9.52 min, [M+H]⁺=424. ¹HNMR δ (ppm) (DMSO-d6): 8.91 (1H, s), 8.22 (1H, d, J=8.10 Hz), 7.09 (1H,dd, J=8.16, 1.68 Hz), 7.00 (1H, d, J=1.64 Hz), 5.49-5.39 (1H, m),4.33-4.27 (2H, m), 3.74 (2H, s), 3.40-3.32 (2H, m), 3.21-3.09 (2H, m),2.92 (1H, s), 1.52 (6H, d, J=6.71 Hz)

Example 120[2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-(2-methoxy-ethyl)-amine120

Following the procedure for 119,2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehydeand 2-methoxyethylamine were reacted. After purification by flashchromatography the resulting oil was dissolved in ether and treated with1M HCl in ether to give a solid that was filtered off and dried to give120 as a yellow solid (129 mg, 56%). LCMS: R_(T)=6.11 min, [M+H]⁺=400.¹H NMR δ (ppm) (DMSO-d6): 9.17 (2H, s), 8.93-8.90 (1H, m), 8.29 (1H, d,J=8.13 Hz), 7.28 (1H, dd, J=8.22, 1.81 Hz), 7.24 (1H, d, J=1.76 Hz),5.47-5.38 (1H, m), 4.33 (2H, t, J=4.98 Hz), 4.10 (2H, t, J=5.38 Hz),3.56 (2H, t, J=5.15 Hz), 3.43-3.30 (2H, m), 3.25 (3H, s), 3.02 (2H, t,J=5.63 Hz), 1.56-1.49 (6H, m)

Example 121Dimethyl-[3-(5-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyridin-2-yloxy)-propyl]-amine121

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted withdimethyl-{3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yloxy]-propyl}-amineto give 121. MS(ESI+) 531.2. ¹H NMR (400 MHz, DMSO) δ 8.56 (d, J=2.2,1H), 8.38 (d, J=8.3, 1H), 8.30 (s, 1H), 8.09 (dd, J=8.7, 2.5, 1H), 7.54(dd, J=8.3, 1.8, 1H), 7.41 (d, J=1.7, 1H), 6.89 (d, J=8.6, 1H), 5.87 (q,J=8.7, 2H), 4.43 (t, J=4.9, 2H), 4.33 (t, J=6.6, 2H), 3.49 (t, J=4.9,2H), 2.37 (t, J=7.1, 2H), 2.16 (s, 6H), 1.87 (p, J=6.8, 2H)

Example 1221-tert-Butyl-5-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-1H-[1,2,4]triazol-3-ylamine122

1-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl)-2-methyl-N-Boc-isothiourea(1.0 g, 2.0 mmol) was dissolved in DMF (5 mL) and treated with DIPEA(1.07 mL, 6.14 mmol). This was followed by the addition oft-butylhydrazine hydrochloride (0.32 g, 2.6 mmol). The reaction mixturewas heated at 85° C. for 2 h. Cooled to r.t. and diluted with EtOAc andH₂O. Extracted twice with EtOAc and the combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Thesolid residue was adsorbed onto Celite and purified by ISCOchromatography (80 g column, 0-100% EtOAc/heptane) to provide[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-tert-butyl-1H-[1,2,4]triazol-3-yl]-carbamicacid tert-butyl ester (940 mg, 90% yield).

[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-tert-butyl-1H-[1,2,4]triazol-3-yl]-carbamicacid tert-butyl ester (0.94 g, 1.8 mmol) was dissolved in MeCN (20 mL)and H₂O (20 mL) and added potassium acetate (601 mg, 6.12 mmol). Thereaction flask was degassed by bubbling N₂ for 5 min. Charged with4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (456 mg,2.53 mmol) and then tetrakis(triphenylphosphine)palladium(0) (280 mg,0.24 mmol). The reaction was subjected to microwave irradiation at 140°C. for 20 min. The reaction was cooled to r.t., filtered through a plugof Celite and diluted with water. Extracted three times with EtOAc andthe combined organic portions were dried over MgSO₄, filtered andconcentrated. The crude residue was taken up in DCM (10 mL) and treatedwith trifluoroacetic acid (5 mL). Stirred at room temperature for 1 hand concentrated in vacuo. The resultant residue was taken up in aminimal amount of DMF/DMSO (1:1) and purified by rp-HPLC to provide 58mg (10% yield) of 122. LC/MS (ESI+): m/z 408 (M+H). ¹H NMR (400 MHz,DMSO) δ 12.96 (bs, 1H), 8.31 (m, 2H), 7.99 (bs, 1H), 7.50-7.39 (m, 2H),7.34 (d, J=1.5, 2H), 5.47 (s, 2H), 4.47-4.24 (m, 4H), 3.39 (dd, J=15.8,10.7, 4H), 1.78 (s, J=18.7, 9H).

Example 123Cyclopentylmethyl-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-amine123

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(360 mg, 0.81 mmol), Pd(OAc)₂ (58 mg, 0.26 mmol),Cyclopentyl-methylamine HCl salt (236 mg, 1.74 mmol),2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol), tert-butoxide (256 mg, 2.61 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 130° C. for 5 min under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-TLC(EtOAc:hexanes=1:1) to afford 51 mg of 123. (yield=13%). ¹H NMR (CDCl₃,400 MHz) δ: 8.01 (s, 1H), 7.50-7.44 (m, 1H), 7.04-6.98 (m, 4H),6.18-6.15 (d, J=8.8 Hz, 1H), 4.16-4.14 (m, 2H), 3.12-3.03 (m, 4H),2.09-2.02 (m, 1H), 1.77-1.70 (m, 2H), 1.60-1.47 (m, 4H), 1.24-1.18 (m,2H). LC-MS (ESI): m/z=480 [M+H]⁺

Example 1241-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperidin-4-ol124

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (49 mg, 0.3 mmol),4-Tri-methylsilanyloxy-piperidine (186 mg, 1.44 mmol),2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 120° C. for 6 min under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford130 mg of 124 (yield=38%). ¹H NMR (MeOD, 400 MHz): δ8.11 (s, 1H),7.68-7.66 (m, 1H), 7.33-7.23 (m, 3H), 7.10-7.08 (m, 1H), 6.54-6.52 (m,1H), 4.16-4.13 (m, 2H), 3.90-3.86 (m, 2H), 3.76-3.72 (m, 2H), 3.07-3.04(m, 2H), 2.95-2.89 (m, 2H), 1.86-1.82 (m, 2H), 1.44-1.41 (m, 2H). LC-MS(ESI): m/z=482 [M+H]⁺

Example 1252-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(1,1-dioxo-S-thiomorpholin-4-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene125

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (49 mg, 0.3 mmol), Thiomorpholine1,1-dioxide (194 mg, 1.44 mmol),2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 120° C. for 1 h under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-TLC(EtOAc:hexanes=1:1) to afford 85 mg of 125. (yield=24%). ¹H NMR (CDCl₃,400 MHz): δ8.03 (s, 1H), 7.52-7.46 (m, 1H), 7.18-7.16 (m, 1H), 7.08-6.95(m, 3H), 4.21-4.19 (m, 2H), 4.05-3.98 (m, 4H), 3.07-3.05 (m, 2H),2.99-2.97 (m, 4H) LC-MS (ESI): m/z=516 [M+H]⁺

Example 126{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-phenethyl-amine126

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (49 mg, 0.3 mmol), phenethylamine (174 mg,1.44 mmol),2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 120° C. for 1 h under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford90 mg of 126 (yield=25%). ¹H NMR (CDCl₃, 400 MHz): δ8.02 (s, 1H),7.47-7.45 (m, 1H), 7.40-7.32 (m, 2H), 7.20-7.12 (m, 2H), 7.09 (s, 1H),7.00-7.90 (m, 3H), 6.11 (d, J=8.4 Hz, 1H), 4.18-4.16 (m, 2H), 3.53-3.47(m, 2H), 3.07-3.03 (m, 2H), 2.87-2.82 (m, 2H). LC-MS (ESI): m/z=502[M+H]⁺

Example 1272-(3-amino-1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxamide127

Similarly to as described in General Procedure D,2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylicacid was reacted with methylamine hydrochloride to give 127 as acolorless solid after reverse phase HPLC (140 mg). LCMS: 454.1

Example 1282-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(2-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene128

To9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 (0.388 g, 0.992 mmol), 2-methylpyridin-3-ylboronic acid(0.176 g, 1.29 mmol), potassium acetate (0.389 g, 3.96 mmol), andtetrakis(triphenylphosphine)palladium(0) (57 mg, 0.049 mmol) was addedDMF (20 mL) and water (1 mL). Nitrogen was bubbled through the reactionmixture for 5 minutes. The reaction mixture was allowed to stir at 105°C. for 24 hours before cooling, diluting with EtOAc, and filteringthrough a pad of celite. The filtrate was concentrated under reducedpressure and diluted with EtOAc. The solution was washed sequentiallywith water, and brine, before drying over MgSO₄ and concentrating underreduced pressure. The crude material was dissolved in DMF and purifiedby reverse phase HPLC to provide 128 (115 mg, 28%). ¹H NMR (400 MHz,DMSO) δ 8.44 (dd, J=24.8, 2.7, 2H), 8.10 (s, 1H), 7.69 (t, J=8.1, 1H),7.35 (ddd, J=12.5, 7.9, 3.6, 2H), 7.19 (d, J=8.3, 1H), 5.74 (dt, J=13.2,6.7, 1H), 4.44 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 2.53 (s, 3H), 1.48(d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).

Example 1292-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(2-methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene129

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 2-methoxypyridin-3-ylboronic acid were reacted. Thecrude material was dissolved in DMF and purified by reverse phase HPLCto provide 129 (200 mg, 60%). ¹H NMR (400 MHz, DMSO) δ 8.66 (d, J=2.2,1H), 8.19 (dd, J=4.9, 1.7, 1H), 8.10 (s, 1H), 7.79 (dd, J=7.3, 1.8, 1H),7.50 (dd, J=8.4, 2.3, 1H), 7.21-7.09 (m, 2H), 5.75 (dt, J=13.3, 6.7,1H), 4.42 (t, J=4.9, 2H), 3.91 (s, 3H), 3.47 (t, J=4.9, 2H), 1.52 (d,J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H).

Example 1302-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(4-methanesulfonyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene130

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperazin-1-yl-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(150 mg, 0.3 mmol) was dissolved in THF, DIPEA (155 mg, 1.2 mmol) wasadded. Methanesulfonyl chloride (41 mg, 0.36 mmol) was added dropwiseinto the solution, and the reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated in vacuo,and then dissolved in DCM. The mixture was washed by water, dried overNa₂SO₄, concentrated in vacuo, and purified by prep. TLC(DCM/EtOAc=10:1) to give 130 (42.0 mg, yield: 26%). ¹HNMR (Acetone, 400MHz): δ8.00 (s, 1H), 7.73-7.71 (m, 1H), 7.36-7.10 (m, 2H), 7.12 (s, 2H),6.69 (d, J=9.2 Hz, 1H), 4.14 (s, 1H), 3.49 (s, 4H), 3.22 (s, 4H), 3.00(s, 2H), 2.79 (s, 3H). ESI-MS: m/z=545 [M+H⁺]

Example 1312-{[2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-amino}-ethanol131

Following the procedure for 119,2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehydeand ethanolamine were reacted. After aqueous work-up the resulting gumwas triturated with DCM/ether/pentane to give a solid that was filteredoff and dried to give 131 as an off-white solid (55 mg, 27%). LCMS:R_(T)=5.54 min, [M+H]⁺=386. ¹H NMR δ (ppm) (CDCl₃): 8.37 (1H, s), 8.30(1H, d, J=8.11 Hz), 7.13 (1H, dd, J=8.15, 1.72 Hz), 7.05 (1H, d, J=1.68Hz), 5.70-5.63 (1H, m), 4.41 (2H, t, J=5.06 Hz), 3.84 (2H, s), 3.68 (2H,t, J=5.17 Hz), 3.42 (2H, t, J=5.07 Hz), 2.85 (2H, t, J=5.16 Hz), 1.65(6H, d, J=6.74 Hz). 2 Exchangeable protons not seen

Example 132{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(2-morpholin-4-yl-ethyl)-amine132

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (49 mg, 0.3 mmol),2-Morpholin-4-yl-ethylamine (200 mg, 1.44 mmol),2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 120° C. for 6 min under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford47 mg of 132. (yield=13%). ¹H NMR (CDCl₃, 400 MHz): δ8.01 (s, 1H),7.50-7.44 (m, 1H), 7.05-6.97 (m, 4H), 6.23-6.21 (d, J=8.4 Hz, 1H),4.76-4.74 (m, 1H), 4.17-4.14 (m, 2H), 3.68-3.66 (m, 4H), 3.30-3.26 (m,2H), 3.04-3.02 (m, 2H), 2.55-2.52 (m, 2H), 2.48-2.42 (m, 4H). LC-MS(ESI): m/z=511 [M+H]⁺

Example 1342-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamine134

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(1.23 g, 3.0 mmol), 4-Methoxy-benzylamine (493 mg, 3.6 mmol), Pd₂(dba)₃(210 mg, 0.3 mmol), Xphos (142 mg, 0.3 mmol), t-BuONa (576 mg, 6 mmol)and dioxane (6 mL) was added in a 10 mL of sealed tube, and the reactionmixture was heated by microwave at 112° C. for 7 min under N₂. Thereaction mixture was filtered to gather the solution. Then water wasadded into the solution and extracted by DCM (50 mL×3). The combinedorganic layer was dried by Na₂SO₄, concentrated in vacuo, separated byTLC (DCM:EtOAc=4:1) to give{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(4-methoxy-benzyl)-amine(1.2 g, yield: 77%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.36 (s, 1H), 7.96 (d,J=2.0 Hz, 1H), 7.69 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.29 (s, 2H),7.14 (s, 1H), 6.97-6.90 (m, 3H), 6.46 (d, J=8.8 Hz, 1H), 4.34 (d, J=6.4Hz, 2H), 4.20 (s, 2H), 3.77 (s, 3H), 3.12 (s, 2H). LC-MS (ESI): m/z=518[M+H]⁺

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(4-methoxy-benzyl)-amine(1.2 g, 2.3 mmol) was dissolved in TFA (20 mL). The reaction mixture wasstirred at 80° C. for 2 h. The reaction mixture was concentrated invacuo, and dissolved in DCM (30 mL). The organic layer was washed bywater, dried by Na₂SO₄, concentrated in vacuo, and separated bypreparative TLC (DCM/EtOAc=4:1) to give 134 (800 mg, yield: 87%)¹H NMR(D₂O, 400 MHz): δ8.05 (s, 2H), 7.05 (d, J=8.8 Hz, 1H), 7.23 (t, J=2.0Hz, 1H), 7.14 (s, 1H), 6.99-6.97 (m, 3H), 6.51 (d, J=8.8 Hz, 1H). LC-MS(ESI): m/z=398 [M+H]⁺

Example 1352-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(6-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene135

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 6-methylpyridin-3-ylboronic acid were reacted. Thecrude material was diluted with DMF and the solids were collected byfiltration to provide 135 (58 mg, 23%). ¹H NMR (400 MHz, DMSO) δ 8.73(dd, J=32.7, 2.1, 2H), 8.11 (s, 1H), 7.96 (dd, J=8.1, 2.4, 1H), 7.65(dd, J=8.4, 2.3, 1H), 7.38 (d, J=8.1, 1H), 7.20 (d, J=8.4, 1H), 5.78(dt, J=13.0, 6.5, 1H), 4.52-4.32 (m, 2H), 3.48 (t, J=4.9, 2H), 2.52 (s,3H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).

Example 1362-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carbonitrile136

9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 (120 mg, 0.31 mmol) was dissolved in DMF (1.6 mL) in a10-mL microwave vial. Purged with N₂ and added zinc cyanide (36 mg, 0.31mmol) followed by tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015mmol). Sealed the vial and evacuated and recycled twice with N₂. Thevessel was subjected to microwave irradiation with stirring for 10 minat 175° C. The vessel was then cooled to r.t. and the reaction mixturewas diluted with dichloromethane and water. The phases were separatedand the organic layer was washed once with water, dried over MgSO₄,filtered and concentrated in vacuo. The crude residue was purified byISCO chromatography (40 g column, 0-10% MeOH/DCM) to provide 76 mg (73%yield) of 136. LC/MS (ESI+): m/z 338 (M+H)

Example 137(S)-1-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-pyrrolidine-2-carbonitrile137

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (S)-pyrrolidine-2-carbonitrile(1.2 equiv) to give 137 (14.2 mg, M+1 392.1)

Example 138((S)-3-Methyl-morpholin-4-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone138

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (S)-3-methylmorpholine (1.2equiv) to give 138 (14.9 mg, M+1 397.1)

Example 1392-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(4-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene139

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 4-methylpyridin-3-ylboronic acid were reacted. Thecrude material was dissolved in DMF and purified by reverse phase HPLCto provide 139 (89 mg, 35%). ¹H NMR (400 MHz, DMSO) δ 8.57-8.29 (m, 3H),8.12 (d, J=15.0, 1H), 7.38 (dd, J=8.3, 2.4, 2H), 7.20 (d, J=8.3, 1H),5.73 (dt, J=13.1, 6.6, 1H), 4.45 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H),2.37 (s, 3H), 1.48 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).

Example 1402-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid isoxazol-3-ylamide 140

To a suspension of2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid (226 mg, 0.63 mmol) in DCM (5 mL) at 0° C. was added DMF (4 drops,catalytic) then oxalyl chloride (115 μL, 1.32 mmol) dropwise. Thereaction mixture was stirred at room temperature for 18 hours.3-Amino-isoxazole (233 μL, 3.15 mmol) was added followed bytriethylamine (176 μL, 1.26 mmol) and the reaction mixture was stirredfor 4 hours. Aqueous saturated sodium bicarbonate solution was added andthen ether and the mixture was filtered. The filtrate was concentratedin vacuo to remove the organics and the resulting aqueous phase wasextracted with DCM (×3). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo. The resultant residue was purifiedby flash chromatography (SiO₂, 0-5% MeOH in EtOAc) then trituration withEtOAc to give 140 as an off-white solid (126 mg, 47%). LCMS: R_(T)=9.86min, [M+H]⁺=423. ¹H NMR δ (ppm) (DMSO-d6): 11.39 (1H, s), 8.94 (1H, s),8.81 (1H, d, J=1.76 Hz), 8.39 (1H, d, J=8.33 Hz), 7.79 (1H, dd, J=8.34,1.90 Hz), 7.70 (1H, d, J=1.87 Hz), 7.00 (1H, d, J=1.76 Hz), 5.51-5.41(1H, m), 4.41-4.35 (2H, m), 3.47-3.41 (2H, m), 1.54 (6H, d, J=6.70 Hz)

Example 141((R)-3-Methyl-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone141

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (R)-3-methylpyrrolidine (1.2equiv) to give 141 (2.4 mg, M+1 381.1)

Example 1428-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-cyano-ethyl)-cyclopentyl-amide 142

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with N-(but-3-ynyl)cyclopentanamine(1.2 equiv) to give 142 (2.4 mg, M+1 434.1)

Example 1432-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-((E)-2-methanesulfonyl-vinyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene143

A mixture of9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 (0.36 g, 0.92 mmol), methyl vinyl sulfone (0.24 mL, 2.8mmol), bis(triphenylphosphine)palladium(II) chloride (64 mg, 0.092 mmol)and triethylamine (0.64 mL, 4.6 mmol) in DMF (10 mL) was heated under anargon atmosphere for 16 h. The reaction mixture was concentrated andpurified by column chromatography (40 g column, 0-100% EtOAc/heptane) toprovide 280 mg (73% yield) of 143. LC/MS (ESI+): m/z 417 (M+H). ¹H NMR(400 MHz, DMSO) δ 8.59 (d, J=2.0, 1H), 8.11 (s, 1H), 7.71 (dd, J=8.4,2.1, 1H), 7.59-7.26 (m, 2H), 7.17 (d, J=8.4, 1H), 5.88-5.67 (m, 1H),4.43 (t, J=4.8, 2H), 3.48 (dd, J=12.3, 7.5, 2H), 3.12 (s, 1H), 1.58 (d,J=6.6, 6H)

Example 1442-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene144

Following the procedure for 114,8-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give144. MS(ESI+) 449.0. ¹H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 8.42 (s,1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.90-7.83 (m, 1H), 7.74-7.66 (m, 1H),7.45-7.35 (m, 2H), 7.26 (d, J=1.5, 1H), 7.16 (dd, J=8.3, 1.6, 1H), 4.33(t, J=4.9, 2H), 3.41 (t, J=4.9, 2H)

Example 1452-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-1H-pyrazol-1-yl)ethanol145

A solution of1-Isopropyl-5-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl]-1H-[1,2,4]triazole(0.23 g, 0.61 mmol) and cesium carbonate (0.40 g, 0.0012 mol) inN,N-dimethylformamide (1.8 mL, 0.023 mol) was stirred at roomtemperature for 5 minutes. 2-Bromoethanol (0.086 mL, 0.0012 mol) wasadded and the reaction was heated to 110° C. overnight. The mixture wascooled to room temperature. Ethyl acetate and water were added and theaqueous layer was extracted 3× with ethyl acetate. The organic phaseswere combined, dried with MgSO₄, and concentrated. The crude waspurified by reverse-phase HPLC to give 101.8 mg of 145 as a colorlesssolid. MS(ESI+) 422.1. ¹H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 8.00 (s,1H), 7.93 (s, 1H), 7.66 (d, J=8.2, 1H), 7.52 (s, 1H), 7.32 (dd, J=8.2,1.6, 1H), 7.27 (d, J=1.5, 1H), 5.10-4.95 (m, 1H), 4.90 (t, J=5.3, 1H),4.34 (t, J=5.0, 2H), 4.15 (t, J=5.6, 2H), 3.77 (q, J=5.5, 2H), 3.29-3.24(m, 2H), 1.48 (d, J=6.5, 6H)

Example 1461-isopropyl-5-(8-(3-(methylsulfonyl)phenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1H-1,2,4-triazole146

Following the procedure for 114, 55-(8-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazolewas reacted with 3-methylsulfonylphenylboronic acid to give 146.MS(ESI+) 466.1.

Example 1473-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)benzoicacid 147

Following the procedure for 114, 55-(8-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazolewas reacted with 3-carboxyphenylboronic acid to give 147. MS(ESI+) 432.1

Example 1488-(3-Methanesulfonyl-phenyl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene148

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with 3-methylsulfonylphenylboronic acid to give 148.MS(ESI+) 507.0. ¹H NMR (400 MHz, DMSO) δ 8.44 (d, J=8.3, 1H), 8.31 (s,1H), 8.25 (s, 1H), 8.14 (d, J=8.0, 1H), 7.93 (d, J=7.8, 1H), 7.75 (t,J=7.8, 1H), 7.67 (dd, J=8.3, 1.7, 1H), 7.55 (d, J=1.7, 1H), 5.88 (q,J=8.6, 2H), 4.45 (t, J=4.9, 2H), 3.52 (t, J=4.9, 2H), 3.32 (s, 3H)

Example 1493-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-benzoicacid 149

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with 3-carboxyphenylboronic acid to give 149. MS(ESI+)473.0. ¹H NMR (400 MHz, DMSO) δ 13.05 (br, 1H), 8.42 (d, J=8.3, 1H),8.30 (s, 1H), 8.24 (s, 1H), 8.00 (d, J=7.8, 1H), 7.96 (d, J=7.8, 1H),7.65-7.54 (m, 2H), 7.42 (d, J=1.6, 1H), 5.88 (q, J=8.6, 2H), 4.45 (t,J=4.9, 2H), 3.51 (t, J=4.9, 2H)

Example 1502-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol150

A solution of8-(1H-Pyrazol-4-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.30 g, 0.00072 mol) and Cesium Carbonate (0.28 g, 0.00086 mol) inN,N-Dimethylformamide (1.5 mL, 0.019 mol) was stirred at roomtemperature for 5 minutes. 2-Bromoethanol (0.061 mL, 0.00086 mol) wasadded and the reaction was stirred at 70° C. overnight. The mixture wascooled to room temperature and ethyl acetate and water were added to thereaction. The aqueous layer was extracted 3 times with ethyl acetate andthe combined organics were washed with water, dried with MgSO₄, andconcentrated. The crude was purified by reverse-phase HPLC to give 150(48.4 mg) as a colorless solid. MS(ESI+) 463.1. ¹H NMR (400 MHz, DMSO) δ8.29 (s, 1H), 8.27 (d, J=8.3, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 7.44 (dd,J=8.3, 1.6, 1H), 7.31 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H), 4.91 (t,J=5.3, 1H), 4.40 (t, J=4.9, 2H), 4.16 (t, J=5.6, 2H), 3.77 (q, J=5.6,2H), 3.47 (t, J=4.9, 2H)

Example 1512-(3-amino-1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxamide151

Similarly to as described in General Procedure D,2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylicacid was reacted with ethanolamine to give 151 as a colorless solidafter reverse phase HPLC (85 mg). LCMS: 484.1

Example 152(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-aceticacid 152

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-aceticacid ethyl ester to give 152. MS(ESI+) 477.0. ¹H NMR (400 MHz, DMSO) δ13.61-12.69 (br, 1H), 8.31-8.26 (m, 2H), 8.25 (s, 1H), 7.99 (s, 1H),7.44 (dd, J=8.3, 1.6, 1H), 7.31 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H),4.95 (s, 2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H)

Example 1538-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-cyano-ethyl)-methyl-amide 153

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 3-(methylamono)propanenitrile(1.2 equiv) to give 153 (32.2 mg, M+1 380.1)

Example 1548-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-methyl-amide 154

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 2-(methylamino)ethanol (1.2equiv) to give 154 (10.4 mg, M+1 371.1)

Example 155Azocan-1-yl-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone155

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with azocane (1.2 equiv) to give155 (12.1 mg, M+1 409.1)

Example 1568-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid ((R)-2-hydroxy-2-phenyl-ethyl)-methyl-amide 156

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(R)-2-(methylamino)-1-phenylethanol (1.2 equiv) to give 156 (19.1 mg,M+1 447.1)

Example 157Azetidin-1-yl-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone157

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with azetidine (1.2 equiv) to give157 (15.9 mg, M+1 353.0)

Example 158[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-pyrrolidin-1-yl-methanone158

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with pyrrolidine (1.2 equiv) togive 158 (17.7 mg, M+1 367.1)

Example 159(4-Methyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone159

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 1-methylpiperazine (1.2 equiv)to give 159 (17.7 mg, M+1 396.0)

Example 160[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone160

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)ethanol (1.2equiv) to give 160 (20.9 mg, M+1 426.1)

Example 161Piperidin-1-yl-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone161

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with piperidine (1.2 equiv) to give161 (17.9 mg, M+1 381.2)

Example 162((R)-2-Hydroxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone162

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (S)-piperidin-2ylmethanol (1.2equiv) to give 162 (12.1 mg, M+1 411.1)

Example 163((R)-3-Methyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone163

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (S)-3-methylpiperidine (1.2equiv) to give 163 (13.8 mg, M+1 395.1)

Example 164(3,3-Dimethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone164

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 3,3-dimethylpiperidine (1.2equiv) to give 164 (12.1 mg, M+1 409.1)

Example 165((R)-3-Hydroxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone165

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (R)-piperidin-3-ylmethanol(1.2 equiv) via to give 165 (18.1 mg, M+1 411.1)

Example 166(4-Hydroxy-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone166

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with piperidin-4-ol (1.2 equiv) togive 166 (16.4 mg, M+1 397.1)

Example 167(4-Methyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone167

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 4-methylpiperidine (1.2 equiv)to give 167 (15.8 mg, M+1 395.1)

Example 168[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4-pyridin-2-yl-piperazin-1-yl)-methanone168

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 1-(pyridine-2-yl)piperazine(1.2 equiv) to give 168 (19.8 mg, M+1 459.1)

Example 1698-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid methyl-(2-pyridin-2-yl-ethyl)-amide 169

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted withN-methyl-2-(pyridine-2-yl)ethanamine (1.2 equiv) to give 169 (14.4 mg,M+1 432.1)

Example 1708-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid methyl-phenethyl-amide 170

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with N-methyl-2-phenylethanamine(1.2 equiv) to give 170 (14.5 mg, M+1 431.1)

Example 171((R)-2-Methyl-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone171

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (S)-2-methylpyrrolidine (1.2equiv) to give 171 (14.8 mg, M+1 381.1)

Example 172((R)-3-Hydroxy-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone172

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (S)-piperidin-3-ol (1.2 equiv)to give 172 (14.1 mg, M+1 397.1)

Example 1738-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid cyclohexyl-(2-hydroxy-ethyl)-amide 173

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 2-(cyclohexylamino)ethanol(1.2 equiv) to give 173 (14.1 mg, M+1 439.1)

Example 1748-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid methyl-[(R)-1-(tetrahydro-furan-2-yl)methyl]-amide 174

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(R)—N-methyl-1(tetrahydrofuran-2-yl)methanamine (1.2 equiv) to give 174(18.4 mg, M+1 411.1)

Example 175(4-Dimethylamino-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone175

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with N,N-dimethylpiperdin-4-amine(1.2 equiv) to give 175 (17.9 mg, M+1 424.1)

Example 176((R)-3-Hydroxy-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone176

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with (R)-pyrrolidin-3-ol (1.2equiv) to give 176 (16.8 mg, M+1 383.1)

Example 177[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4-pyrimidin-2-yl-piperazin-1-yl)-methanone177

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)pyrimidine(1.2 equiv) to give 177 (8.7 mg, M+1 460.1)

Example 178[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-methanone178

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)pyrazine(1.2 equiv) to give 178 (8.7 mg, M+1 460.1)

Example 1791-{4-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperazin-1-yl}-ethanone179

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 1-(piperazin-1-yl)ethanone(1.2 equiv) to give 179 (13.5 mg, M+1 424.1)

Example 180N-Methyl-N-{(R)-1-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-pyrrolidin-3-yl}-acetamide180

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(R)—N-methyl-N-(pyrrolidin-3-yl)acetamide (1.2 equiv) to give 180 (24.3mg, M+1 438.1)

Example 1818-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid ((R)-2,3-dihydroxy-propyl)-methyl-amide 181

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(S)-3-(methylamino)propane-1,2-diol (1.2 equiv) to give 181 (14.9 mg,M+1 401.1)

Example 1828-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-methoxy-ethyl)-methyl-amide 182

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 2-methoxy-N-methylethanamine(1.2 equiv) to give 182 (15.1 mg, M+1 385.1)

Example 183(4-Hydroxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone183

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with piperidin-4-ylmethanol (1.2equiv) to give 183 (15.9 mg, M+1 411.1)

Example 184[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-[4-((R)-tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-methanone184

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted withpiperazin-1-yl(tetrahydrofuran-2-yl)methanone (1.2 equiv) to give 184(19.3 mg, M+1 480.1)

Example 185[4-(2-Methoxy-ethyl)-piperazin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone185

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 1-(2-methoxyethyl)piperazine(1.2 equiv) to give 185 (21.8 mg, M+1 440.1)

Example 186[4-(2-Methoxy-phenyl)-piperidin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone186

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 4-(2-methoxyphenyl)piperidine(1.2 equiv) to give 186 (17.9 mg, M+1 487.1)

Example 1878-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid [(R)-1-(2,3-dihydro-benzofuran-2-yl)methyl]-methyl-amide 187

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(R)-1-(2,3-dihydrobenzofuran-2-yl)-N-methylmethanamine (1.2 equiv) togive 187 (16.8 mg, M+1 459.1)

Example 1882-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-ethanol188

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol),Trimethylsilanyloxy-ethylamine (190 mg, 1.44 mmol), X-phos (70 mg, 0.144mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbledN₂ for 10 min and then stirred at 120° C. for 6 min under the irraditionof microwave. The mixture was filtered over celite. The filtrate wasconcentrated to dryness and purified by pre-HPLC to afford 64.8 mg of188. (yield=21%). ¹H NMR (CDCl₃, 400 MHz): δ8.02 (s, 1H), 7.51-7.45 (m,1H), 7.08-7.00 (m, 4H), 6.24-6.22 (d, J=8.8 Hz, 1H), 4.17-4.15 (m, 2H),3.76-3.74 (m, 2H), 3.45-3.42 (m, 2H), 3.06-3.04 (m, 2H). LC-MS (ESI):m/z=442 [M+H]⁺

Example 1902-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(1-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene190

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(100 mg, 0.24 mmol), Cs₂CO₃ (156.4 mg, 0.48 mmol), Pd(dppf)Cl₂ (17 mg,0.024 mmol) and1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(65 mg, 0.30 mmol) in acetonitrile/water (3 mL, 3:1) was degassed withN₂ for 2 min, then stirred at 150° C. for 15 min under the irradition ofmicrowave. The mixture was filtered over ceilite. The filtrate wasconcentrated to dryness and purified by pre-TLC to afford 23 mg of 190(yield=21%). ¹H NMR (MeOD, 400 MHz): δ8.19 (s, 1H), 7.94 (s, 1H), 7.85(s, 1H), 7.68-7.62 (m, 2H), 7.44-7.24 (m, 5H), 4.31-4.28 (m, 2H), 3.95(s, 3H), 3.16-3.14 (m, 2H) LC-MS (ESI): m/z=463 [M+H]⁺

Example 1912-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(5-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene191

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 5-methylpyridin-3-ylboronic acid were reacted to give191 (0.027 g, 17%). ¹H NMR (400 MHz, DMSO) δ 8.73 (d, J=2.4, 2H), 8.42(s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.69 (dd, J=8.4, 2.3, 1H), 7.20 (d,J=8.4, 1H), 5.82 (dt, J=13.1, 6.5, 1H), 4.43 (t, J=4.8, 2H), 3.56-3.39(m, 2H), 2.39 (s, 3H), 1.58 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.0 (M+H)

Example 1924-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-benzenesulfonamide192

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 4-sulfamoylphenylboronic acid were reacted to give192 (0.034 g, 19%). ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J=2.3, 1H), 8.02(d, J=8.4, 2H), 7.94 (s, 1H), 7.75 (t, J=12.6, 2H), 7.51 (dt, J=13.0,6.5, 1H), 7.19 (d, J=8.4, 1H), 5.86 (dt, J=13.3, 6.7, 1H), 4.82 (s, 2H),4.47 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 1.65 (d, J=6.6, 6H). MS(ESI(+)): m/z 468.1 (M+H)

Example 1932-Methyl-1-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propan-2-ol193

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 193. MS(ESI+) 491.1. ¹H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.27(d, J=8.3, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.45 (dd, J=8.3, 1.8, 1H),7.31 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.71 (s, 1H), 4.39 (t, J=5.0,2H), 4.03 (s, 2H), 3.47 (t, J=5.0, 2H), 1.10 (s, 6H)

Example 194(4-Benzoyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone194

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted withphenyl(piperazin-1-yl)methanone (1.2 equiv) to give 194 (M+1 486.0)

Example 195(4-Cyclopropylmethyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone195

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with1-(cyclopropylmethyl)piperazine (1.2 equiv) to give 195 (M+1 436.0)

Example 1964-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperazine-1-carboxylicacid dimethylamide 196

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted withN,N-dimethylpiperazine-1-carboxamide (1.2 equiv) to give 196 (M+1 453.0)

Example 197(R)-Octahydro-pyrido[1,2-a]pyrazin-2-yl-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone197

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.2 equiv) to give 197 (M+1436.0)

Example 198[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone198

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with1-(6-methylpyridin-2-yl)piperazine (1.2 equiv) to give 198 (M+1 473.0)

Example 199[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-{4-[(R)-1-(tetrahydro-furan-2-yl)methyl]-piperazin-1-yl}-methanone199

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(S)-1-((tetrahydrofuran-2-yl)methyl)piperazine (1.2 equiv) to give 199(M+1 466.0)

Example 200(4-Methanesulfonyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone200

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 1-(methylsulfonyl)piperazine(1.2 equiv) to give 200 (M+1 460.0)

Example 201[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-((R)-3-trifluoromethyl-piperidin-1-yl)-methanone201

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(R)-3-(trifluoromethyl)piperidine (1.2 equiv) to give 201 (M+1 449.0)

Example 202((R)-3-Diethylamino-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone202

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(R)—N,N-diethylpyrrolidin-3-amine (1.2 equiv) to give 202 (M+1 438.0)

Example 203(4,4-Difluoro-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone203

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 4,4-difluoropiperidine (1.2equiv) to give 203 (M+1 417.0)

Example 204[4-((2R,6R)-2,6-Dimethyl-morpholin-4-yl)-piperidin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone204

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(3S,5S-3,5-dimethyl-4-(piperidin-4-yl)morpholine (1.2 equiv) to give 204(M+1 494.0)

Example 205[4-(4-Methyl-piperazine-1-carbonyl)-piperidin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone205

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(4-methylpiperazin-1-yl)(piperidin-4-yl)methanone (1.2 equiv) to give205 (M+1 507.0)

Example 206[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-[4-(pyrrolidine-1-carbonyl)-piperidin-1-yl]-methanone206

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted withpiperidin-4-yl(pyrrolidin-1-yl)methanone (1.2 equiv) to give 206 (M+1478.0)

Example 207(4-Cyclopropanecarbonyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone207

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted withcyclopropyl(piperidin-4-yl)methanone (1.2 equiv) to give 207 (M+1 450.0)

Example 208[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4-pyridin-4-yl-[1,4]diazepan-1-yl)-methanone208

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 1-(pyridin-4-yl)-1,4-diazepane(1.2 equiv) to give 208 (M+1 473.0)

Example 2098-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 209

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 2-(isopropylamino)ethanol (1.2equiv) to give 209 (10.8 mg, M+1 399.1)

Example 210((R)-3-Dimethylamino-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone210

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(R)—N,N-dimethylpyrrolidin-3amine (1.2 equiv) to give 210 (M+1 410.0)

Example 2112-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionicacid 211

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with2-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionicacid ethyl ester to give 211. MS(ESI+) 505.1

Example 2122-{[2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-amino}-acetamide212

To a suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde(86 mg, 0.25 mmol) in MeOH (4 mL) was added glycinamide hydrochloride(140 mg, 1.26 mmol) and the mixture was stirred for 30 minutes. AcOH (2drops) was added followed by sodium borohydride (14 mg, 0.38 mmol) andthe reaction mixture was stirred for 65 hours. Further sodiumborohydride (10 mg) was added and the reaction stirred for another 20hours. Aqueous saturated sodium bicarbonate solution (15 mL) was addedand the MeOH was removed in vacuo. The aqueous phase was extracted withDCM (×3) and the combined organic phase was dried (Na₂SO₄) andconcentrated in vacuo. The resultant residue was purified by flashchromatography (SiO₂, 0-6% MeOH in EtOAc then 0-5% 2M NH₃/MeOH in DCM)to give 212 as a yellow solid (30 mg, 30%). LCMS: R_(T)=5.43 min,[M+H]⁺=399. ¹H NMR δ (ppm) (DMSO-d6): 8.93 (1H, s), 8.23 (1H, d, J=8.10Hz), 7.25 (1H, s), 7.11 (1H, dd, J=8.16, 1.70 Hz), 7.01 (1H, d, J=1.75Hz), 5.52-5.40 (1H, m), 4.33 (2H, t, J=5.05 Hz), 3.65 (2H, s), 3.39 (2H,t, J=5.11 Hz), 3.01 (2H, s), 1.54 (6H, d, J=6.71 Hz)

Example 213[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-((R)-3-trifluoromethyl-pyrrolidin-1-yl)-methanone213

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with(S)-3-(trifluoromethyl)pyrrolidine (1.2 equiv) to give 213 (15.8 mg, M+1435.1)

Example 214[4-(2,4-Difluoro-phenyl)-piperidin-1-yl]-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone214

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with4-(2,4-difluorophenyl)piperidine (1.2 equiv) to give 214 (11.8 mg, M+1493.1)

Example 215(4-Methoxy-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone215

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with 4-methoxypiperidine (1.2equiv) to give 215 (19.6 mg, M+1 411.1)

Example 216[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-((R)-2-pyridin-2-ylmethyl-pyrrolidin-1-yl)-methanone216

Following Example 103, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50 mg, 0.20 mmol) in DMF at room temperature was added(R)-2-(pyrrolidin-2-ylmethyl)pyridine (0.24 mmol), followed by theaddition of DIPEA (0.056 ml, 0.32 mmol). Finally, HATU (0.067 grams,0.18 mmol) was added and the reaction mixture was heated as a slurry at50 C for 4 hours. The reaction mixture was conc. in vacuo and taken intoa large volume of EtOAc and the organic phase was washed with diluteaqueous bicarb, water and then saline and dried (Na2SO4), thenconcentrated to a residue. The crude material was purified bypreparative RP-HPLC to give 216 as a lyophilized solid. MS: (ESI+)=458.5

Example 2174-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperazine-1-sulfonicacid dimethylamide 217

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and N,N-dimethylpiperazine-1-sulfonamide were reacted to give 217.MS: (ESI+)=489.1

Example 2182-Methyl-1-{4-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperazin-1-yl}-propan-1-one218

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and N,N-dimethylpiperazine-1-carboxamide were reacted to give 218.MS: (ESI+)=452.1

Example 219((R)-3-Methoxy-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone219

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and (R)-2-methoxypiperidine were reacted to give 219. MS:(ESI+)=411.1

Example 2201-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperidine-4-carbonitrile220

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and piperidine-4-carbonitrile were reacted to give 220. MS:(ESI+)=406.0

Example 221(3,3-Difluoro-azetidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone221

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 3,3-difluoroazetidine to give 221. MS: (ESI+)=389.0

Example 2228-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid ((S)-1-isopropyl-pyrrolidin-3-ylmethyl)-methyl-amide 222

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and (S)-1-(1-isopropylpyrrolidin-3-yl)-N-methylmethanamine to give222. MS: (ESI+)=452.2

Example 223((R)-3-Methoxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone223

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and (S)-3-(methoxymethyl)piperidine to give 223. MS: (ESI+)=425.1

Example 224(4-Methoxymethyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone224

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 4-(methoxymethyl)piperidine to give 224. MS: (ESI+)=425.1

Example 2258-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid methyl-(2-morpholin-4-yl-2-oxo-ethyl)-amide 225

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 2-(methylamino)-1-morpholinoethanone to give 225. MS:(ESI+)=454.1

Example 226[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4-pyridin-3-yl-piperazin-1-yl)-methanone226

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 1-(pyridin-2-yl)piperazine to give 226. MS: (ESI+)=459.2

Example 227[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-(4-pyridin-2-yl-[1,4]diazepan-1-yl)-methanone227

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 1-(pyridin-2-yl)-1,4-diazepane to give 227. MS: (ESI+)=473.1

Example 228((R)-3-Morpholin-4-yl-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone228

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and (R)-4-(pyrrolidin-3-yl)morpholine to give 228. MS: (ESI+)=453.1

Example 2292,2,2-Trifluoro-1-{4-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperazin-1-yl}-ethanone229

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 2,2,2-trifluoro-1-(piperazin-1-yl)ethanone to give 229. MS:(ESI+)=478.1

Example 2302-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(4-methanesulfonyl-phenyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene230

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 4-(methylsulfonyl)phenylboronic acid were reacted togive 230 (0.072 g, 40%). ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=2.3, 1H),8.03 (d, J=8.4, 2H), 7.94 (s, 1H), 7.82 (d, J=8.4, 2H), 7.59-7.48 (m,1H), 7.20 (d, J=8.4, 1H), 5.94-5.79 (m, 1H), 4.48 (t, J=4.9, 2H), 3.46(dd, J=10.7, 5.8, 2H), 3.12 (s, 3H), 1.65 (d, J=6.6, 6H). MS (ESI(+)):m/z 467.1 (M+H)

Example 231{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-[2-(4-methyl-piperazin-1-yl)-ethyl]-amine231

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol),2-(4-methylpiperazin-1-yl)ethanamine (121 mg, 0.936 mmol), X-phos (70mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 120° C. for 5 min under theirradiation of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford180 mg of 231. (yield=48%). ¹H NMR (CDCl₃, 400 MHz): δ8.41 (s, 1H), 8.01(m, 1H), 7.50-7.45 (m, 1H), 7.06-6.99 (m, 3H), 6.88 (s, 1H), 6.24 (d,J=8.8 Hz, 1H), 4.16-4.14 (m, 2H), 3.42-3.40 (m, 2H), 3.02-3.00 (m, 2H),2.82-2.70 (m, 10H), 2.42 (s, 3H). LC-MS (ESI): m/z=524 [M+H]⁺

Example 2322-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene232

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene,from the procedure for 249, (470 mg, 1.0 mmol), Piperidine (102 mg, 1.2mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL ofsealed tube, and the mixture was heated by microwave at 150° C. for 120min under N₂. The reaction mixture was filtered to gather the solutionand water was added. The mixture was extracted by DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, concentrated in vacuo,and purified by preparative HPLC to give 232 (46.2 mg, yield: 8.5%).¹HNMR (DMSO-d₆, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.10 (d, J=4.8Hz, 1H), 7.91-7.87 (m, 1H), 7.78-7.77 (m, 2H), 7.50-7.40 (m, 1H), 7.18(d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.31(s, 2H), 3.64 (s, 4H), 3.16 (s, 2H), 1.63-1.57 (m, 4H) ESI-MS: m/z=543[M+H⁺]

Example 2332-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene233

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (282mg, 1.2 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10 mmol)and CH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube, and themixture was heated by microwave at 120° C. for 20 min under N₂. Thereaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to give 233 (87.2 mg, yield: 17%). ¹HNMR (DMSO-d₆, 400MHz): δ8.81 (s, 1H), 8.31 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.85 7.78 (m,2H), 7.49 (d, J=2.4 Hz, 2H), 7.21 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 4.27(s, 2H), 3.93 (s, 3H), 3.17 (s, 2H). ESI-MS: m/z=490 [M+H⁺]

Example 2342-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(2-methoxy-phenyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene234

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 2-methoxyphenylboronic acid were reacted to give 234(0.087 g, 54%). ¹H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 8.10 (s, 1H),7.39 (dd, J=31.7, 7.5, 3H), 7.09 (dt, J=14.7, 9.8, 3H), 5.82-5.69 (m,1H), 4.41 (s, 2H), 3.79 (s, 3H), 3.47 (s, 2H), 1.51 (d, J=6.5, 6H). MS(ESI(+)): m/z 419.1 (M+H)

Example 2358-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene235

A solution of3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.1 mmol) in DCM (6.5 mL) was treated withTFA (6.5 mL). The reaction mixture was stirred at RT for 4 hours thenconcentrated in vacuo. The residue was azeotroped with DCM thendissolved in DCM and washed with an aqueous saturated sodium bicarbonatesolution (×2) followed by brine. The mixture was passed through a phaseseparator cartridge and concentrated in vacuo to give 235 as a paleorange gum (397 mg, quant.). LCMS: R_(T)=3.13 min, [M+H]⁺=368. 1H NMR δ(ppm) (DMSO-d6): 9.34 (1H, s), 9.05 (1H, s), 8.30 (1H, d, J=8.19 Hz),8.06 (1H, d, J=0.58 Hz), 7.23 (1H, dd, J=8.24, 1.89 Hz), 7.13 (1H, d,J=1.84 Hz), 5.82-5.72 (1H, m), 4.36-4.30 (2H, m), 4.25-4.17 (2H, m),4.13-3.97 (3H, m), 3.43-3.37 (2H, m), 1.50 (6H, d, J=6.59 Hz).

Example 2363-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidine-1-carboxylicacid tert-butyl ester 236

Zinc (151 mg, 2.31 mmol) was stirred in DMA (0.4 mL) under an atmosphereof argon. Chlorotrimethylsilane (25 uL, 0.20 mmol) and 1,2-dibromoethane(20 uL, 0.2 mmol) were added (gentle exotherm) and the mixture stirredat room temperature for 15 min. A solution of tert-butyl3-iodoazetidine-1-carboxylate (0.5 g, 1.8 mmol) in DMA (1 mL) wasintroduced and the reaction was allowed to stir at room temperature foran additional 30 min. Meanwhile,[1,1′-Bis(diphenylphosphino)ferrocen]dichloropalladium(II), in complexwith dichloromethane (1:1) (68 mg, 0.083 mmol), copper(I) iodide (32 mg,0.166 mmol) and9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 (0.65 g, 1.66 mmol) were mixed in DMA (2.5 mL) andstirred under argon for 10 min. Subsequently, the organozinc reagentsolution was transferred to this mixture via syringe. The resultinggreen reaction mixture was stirred at 80° C. whereupon it turned yellow.Stirring was continued for 20 h. At this point, LCMS indicatedapproximately 33% conversion to the title compound. The mixture wasdiluted with EtOAc (25 mL) and 1 N HCl (25 mL) and the layers werepartitioned. The aqueous layer was extracted with EtOAc (2×10 mL) andthe combined organic portions were washed once with brine. The extractwas dried over MgSO₄ and concentrated in vacuo. The residue was purifiedby rp-HPLC to give 236 (35 mg, 5% yield). LC/MS (ESI+): m/z 468.2 (M+H).¹H NMR (400 MHz, DMSO) δ 1.22 8.47 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.20(dd, J=8.2, 2.1 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 5.84 (dt, J=13.2, 6.5Hz, 1H), 4.35 (dd, J=17.3, 12.5 Hz, 4H), 3.82 (s, 3H), 3.44 (t, J=4.9Hz, 2H), 1.58 (t, J=9.5 Hz, 6H), 1.41 (s, 9H).

Example 2372-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(5-methanesulfonyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene237

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 5-(methylsulfonyl)pyridin-3-ylboronic acid werereacted to give 237 (0.053 g, 30%). ¹H NMR (400 MHz, DMSO) δ 9.28 (d,J=2.0, 1H), 9.07 (d, J=1.8, 1H), 8.82 (d, J=2.2, 1H), 8.56 (s, 1H), 8.11(s, 1H), 7.87 (dd, J=8.4, 2.3, 1H), 7.27 (d, J=8.4, 1H), 5.87 (dt,J=13.0, 6.5, 1H), 4.45 (t, J=4.8, 2H), 3.50 (t, J=4.8, 2H), 3.41 (s,3H), 1.59 (d, J=6.6, 6H). MS (ESI(+)): m/z 468.1 (M+H)

Example 2388-(1-Methanesulfonyl-1H-pyrazol-4-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene238

To a round bottom flask containing8-(1H-Pyrazol-4-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.200 g, 0.000478 mol) in methylene chloride (3 mL, 0.05 mol) andchloroform (2 mL, 0.02 mol) was added triethylamine (0.080 mL, 0.00057mol) and methanesulfonyl chloride (0.088 mL, 0.00114 mol). The reactionwas stirred at 40° C. for 6 h. The mixture was washed with waterfollowed by brine, dried with MgSO₄ and concentrated. The crude wasloaded as a solid onto silica gel and purified by flash chromatography(1-10% MeOH in DCM) followed by reverse-phase HPLC to give 238 (16.5 mg)as a colorless solid. MS(ESI+) 497.0. ¹H NMR (400 MHz, DMSO) δ 8.88 (s,1H), 8.56 (s, 1H), 8.33 (d, J=8.3, 1H), 8.30 (s, 1H), 7.65 (dd, J=8.3,1.6, 1H), 7.55 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H), 4.42 (t, J=4.9, 2H),3.58 (s, 3H), 3.49 (t, J=4.9, 2H)

Example 2399-(2-Isopropoxy-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene239

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and2-isopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinewere reacted to give 239 (0.102 g, 59%). ¹H NMR (400 MHz, DMSO) δ 8.53(d, J=2.2, 1H), 8.23-8.03 (m, 2H), 7.75 (dd, J=7.3, 1.8, 1H), 7.56 (dd,J=8.4, 2.2, 1H), 7.20-7.00 (m, 2H), 5.72 (dt, J=13.3, 6.6, 1H), 5.35(dt, J=12.3, 6.2, 1H), 4.43 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 1.50(d, J=6.6, 6H), 1.29 (d, J=6.2, 6H). MS (ESI(+)): m/z 448.1 (M+H)

Example 2402-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-acetamide240

To a round bottom flask containing(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-aceticacid (0.150 g, 0.000315 mol) in tetrahydrofuran (2.0 mL, 0.025 mol) wasadded N,N-diisopropylethylamine (0.33 mL, 0.0019 mol), ammonium chloride(0.10 g, 0.0019 mol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) (0.24 g, 0.00063 mol). The reaction wasstirred at room temperature overnight. The mixture was partitionedbetween saturated sodium bicarbonate and ethyl acetate. The organicphases were combined, dried with MgSO₄, and concentrated. The crude waspurified by reverse-phase HPLC to yield 240 (31.5 mg) as a colorlesssolid. MS(ESI+) 476.1.

Example 241N,N-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-acetamide241

Following the procedure for 240,(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-aceticacid was reacted with dimethylamine to give 241. MS(ESI+) 504.1. ¹H NMR(400 MHz, DMSO) δ 8.31-8.26 (m, 2H), 8.16 (s, 1H), 7.97 (s, 1H), 7.44(dd, J=8.3, 1.6, 1H), 7.31 (d, J=1.4, 1H), 5.87 (q, J=8.7, 2H), 5.12 (s,2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 3.05 (s, 3H), 2.87 (s,3H)

Example 2422-({2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-methyl-amino)-ethanol242

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol),Methyl-(2-trimethylsilanyloxy-ethyl)-amine (211 mg, 1.44 mmol), X-phos(70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL)was bubbled N₂ for 10 min and then stirred at 125° C. for 7 min underthe irradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-TLC(EtOAc:PE=2:1) to afford 85 mg of 242. (yield=26%). ¹H NMR (CDCl₃, 400MHz): δ8.01-8.00 (m, 1H), 7.50-7.45 (m, 1H), 7.13-7.00 (m, 4H), 6.36 (d,J=9.2 Hz, 1H), 4.17-4.15 (m, 2H), 3.78-3.75 (m, 1H), 3.63-3.59 (m, 2H),3.07-3.05 (m, 2H), 2.98 (s, 3H), 2.30-2.26 (m, 1H). LC-MS (ESI): m/z=456[M+H]⁺

Example 2432-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(4-isopropyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene243

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol), 1-Isopropyl-piperazine(164 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg,1.44 mmol) in dioxane (2 mL) was bubbled N₂ for 10 min and then stirredat 120° C. for 2.5 min under the irradition of microwave. The mixturewas filtered over celite. The filtrate was concentrated to dryness andpurified by pre-HPLC to afford 80 mg of 243. (yield=22%). ¹H NMR (CDCl₃,400 MHz): δ8.02 (s, 1H), 7.50-7.44 (m, 1H), 7.09-6.99 (m, 4H), 6.46 (d,J=8.8 Hz, 1H), 4.18-4.12 (m, 2H), 3.42-3.40 (m, 3H), 3.05-3.03 (m, 2H),2.12-2.06 (m, 2H), 1.56-1.50 (m, 3H), 1.10-1.04 (m, 3H). LC-MS (ESI):m/z=509 [M+H]⁺

Example 2444-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-butan-2-ol244

Following the procedures for 246,4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-but-3-yn-2-olwas prepared (Yield: 93%. ¹H NMR (DMSO-d₆, 400 MHz): δ8.32 (s, 1H), 7.93(dd, J=5.6, 8.4 Hz, 1H), 7.74-7.69 (m, 1H), 7.45-7.40 (m, 2H), 7.33 (d,J=8.0 Hz, 1H), 6.95 (s, 1H), 5.59 (d, J=5.2 Hz, 1H), 4.64 (q, J=5.6, 6.8Hz, 1H), 4.32 (t, J=4.0 Hz, 2H), 3.13 (t, J=4.4 Hz, 2H), 1.42 (d, J=6.4Hz, 3H), ESI-MS: (m/z)=451 [M+H]⁺) from9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azuleneand but-3-yn-2-ol, and hydrogenated to give 244 Yield: 38%. ¹H NMR(DMSO-d₆, 400 MHz): δ8.26 (s, 1H), 7.89-7.84 (m, 1H), 7.70-7.65 (m, 1H),7.40 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H),7.00 (s, 1H), 4.44 (s, 1H), 4.23 (t, =4.8 Hz, 2H), 3.58-3.56 (m, 1H),3.13 (t, J=4.8 Hz, 2H), 2.71-2.63 (m, 2H), 1.69-1.61 (m, 2H), 1.05 (d,J=6.4 Hz, 3H). LC-MS (ESI): m/z=455 [M+H]⁺

Example 2454-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-butan-1-ol245

Following the procedures for 246,9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azuleneand but-3-yn-1-ol were reacted under palladium catalysis to give4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-but-3-yn-1-ol(Yield: 81%. ¹H NMR (DMSO-d₆, 400 MHz): δ8.31 (s, 1H), 7.94-7.88 (m,1H), 7.74-7.68 (m, 1H), 7.43-7.38 (m, 2H), 7.31 (d, J=8.4 Hz, 1H), 6.92(s, 1H), 4.95 (s, 1H), 4.31 (t, J=4.0 Hz, 2H), 3.62 (m, 2H), 3.12 (t,J=4.4 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H). LC-MS (ESI): m/z=451 [M+H]⁺),which was hydrogenated to give 245 Yield: 43%. ¹H NMR (DMSO-d₆, 400MHz): δ8.27 (s, 1H), 7.90-7.84 (m, 1H), 7.70-7.65 (m, 1H), 7.41-7.39 (m,1H), 7.29 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 4.37(s, 1H), 4.23 (t, J=4.8 Hz, 2H), 3.40 (t, J=6.4 Hz, 2H), 3.09 (t, J=4.8Hz, 2H), 2.64-2.60 (m, 2H), 1.65-1.59 (m, 1H), 1.44-1.38 (m, 1H). LC-MS(ESI): m/z=455 [M+H]⁺

Example 246(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-propyl)-dimethyl-amine246

To a mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(500 mg, 1.2 mmol), and dimethyl-prop-2-ynyl-amine (150 mg, 1.8 mmol) indry DMF (3 mL) under nitrogen was added K₂CO₃ (498 mg, 3.6 mmol), CuI(11 mg, 0.06 mmol), 1,3-bis(diphenylphosphino)propane (99 mg, 0.24 mmol)and Pd(OAc)₂ (27 mg, 0.12 mmol). The reaction mixture was heated at 110°C. for 40 min under microwave. Cooled to room temperature, the resultingmixture was poured into water and extracted with EtOAc. Dried organicsover sodium sulfate and purified by column chromatography(Hexanes/EtOAc=1:1) to give(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-prop-2-ynyl)-dimethyl-amineas a yellow solid (530 mg, yield 95%). ¹H NMR (DMSO-d₆, 400 MHz): δ8.31(s, 1H), 7.91 (dd, J=3.2, 8.8 Hz, 1H), 7.73-7.68 (m, 1H), 7.40 (d, J=8.0Hz, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 4.31 (t, J=4.8 Hz, 2H),3.50 (s, 2H), 3.14 (t, J=4.8 Hz, 2H), 2.27 (s, 6H). ESI-MS: (m/z)=464[M+H]⁺

The mixture of(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-prop-2-ynyl)-dimethyl-amine(200 mg, 0.43 mmol), 10% Pd/C (20 mg) in MeOH (20 mL) was stirred underH₂ atmosphere (50 psi) at room temperature for overnight. Filtered andconcentrated to give 246 (26 mg, yield: 13%). ¹H NMR (CDCl₃, 400 MHz):δ8.08 (s, 1H), 7.58-7.52 (m, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.15-7.07 (m,2H), 6.94 (d, J=8.0 Hz, 1H), 6.90 (s, 1H), 4.29 (t, J=4.4 Hz, 2H), 3.12(t, J=4.4 Hz, 2H), 2.82-2.77 (m, 4H), 2.57 (s, 6H), 2.15-2.08 (m, 2H).ESI-MS: (m/z)=468 [M+H]⁺

Example 247N-(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-acetamide247

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),N-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-acetamide(314 mg, 1.2 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10mmol) and CH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube,and the mixture was heated by microwave at 120° C. for 20 min under N₂.The reaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to 247 (77 mg, yield: 15%). ¹HNMR (DMSO-d₆, 400 MHz):δ10.62 (s, 1H), 8.88 (s, 1H), 8.27 (s, 1H), 8.15 (s, 2H), 7.42 (t, J=0.8Hz, 1H), 7.89-7.81 (m, 3H), 7.47 (t, J=8.8 Hz, 2H), 7.15 (s, 1H), 4.27(s, 2H), 3.17 (s, 2H), 2.08 (s, 3H). ESI-MS: m/z=517 [M+H⁺]

Example 2482-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-morpholin-4-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene248

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(4.16 mg, 10 mmol),4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-morpholine(350 mg, 12 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10mmol) and CH₃CN—H₂O (1:1, 4 mL) were added in a 50 mL of sealed tube,and the mixture was heated by microwave at 80° C. for 60 min under N₂.The reaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (50 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative TLC to give 248 (98.1 mg, yield: 18%). ¹HNMR (DMSO-d₆, 400MHz): δ8.75 (s, 1H), 8.28 (s, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.73-7.71 (m,1H), 7.45-7.41 (m, 2H), 7.41-7.38 (m, 2H), 7.14 (s, 1H), 6.93 (d, J=8.8Hz, 1H), 4.27 (s, 2H), 3.74 (s, 4H), 3.53 (s, 4H), 3.11 (s, 2H). ESI-MS:m/z=545 [M+H⁺]

Example 2492-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene249

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(4.16 g, 10 mmol),2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (2.67g, 12 mmol), Cs₂CO₃ (6.50 g, 20 mmol), Pd(dppf)Cl₂ (730 mg, 1.0 mmol)and CH₃CN—H₂O (1:1, 40 mL) were added in a 50 mL of sealed tube, and themixture was heated at 80° C. for 60 min under N₂. The reaction mixturewas filtered to gather the solution and water was added. The mixture wasextracted by DCM (50 mL×3). The combined organic layers were dried overNa₂SO₄, concentrated in vacuo, and purified by preparative TLC to give2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(4.0 g, yield: 84%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.68 (s, 1H), 8.43 (t,J=4.8 Hz, 2H), 8.12-8.01 (m, 1H), 8.00-7.92 (m, 1H), 7.84 (t, J=2.8 Hz,1H), 7.58-7.50 (m, 2H), 7.26 (s, 2H), 4.39 (s, 2H), 3.24 (s, 2H), 2.23(s, 3H). ESI-MS: m/z=478 [M+H⁺]

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(470 mg, 1.0 mmol), 1-Methyl-piperazine (120 mg, 1.2 mmol), DIPEA (340mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and themixture was heated by microwave at 150° C. for 120 min under N₂. Thereaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to give 249 (315 mg, yield: 57%). ¹HNMR (DMSO-d₆, 400MHz): δ8.71 (s, 1H), 8.27 (s, 1H), 8.04 (d, J=3.2 Hz, 1H), 7.42 (t, J=2Hz, 1H), 7.90-7.88 (m, 1H), 7.76-7.78 (m, 2H), 7.46-7.40 (m, 1H), 7.38(d, J=8.4 Hz, 1H), 7.14 (m, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.26 (s, 2H),3.50 (s, 3H), 3.10 (s, 2H), 2.38 (s, 4H), 2.18 (s, 3H). ESI-MS: m/z=558[M+H⁺]

Example 250{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(tetrahydro-pyran-4-yl)-amine250

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol),Tetrahydro-pyran-4-ylamine (145 mg, 1.44 mmol), X-phos (70 mg, 0.144mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbledN₂ for 10 min and then stirred at 120° C. for 2.5 min under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford80 mg of 250. (yield=29%). ¹H NMR (CDCl₃, 400 MHz): δ8.03 (s, 1H),7.50-7.44 (m, 1H), 7.09-6.99 (m, 4H), 6.18 (d, J=8.8 Hz, 1H), 4.06-4.02(m, 1H), 3.96-3.90 (m, 2H), 3.84-3.76 (m, 1H), 3.50-3.41 (m, 2H),3.06-3.03 (m, 2H), 1.48-1.40 (m, 2H). LC-MS (ESI): m/z=481 [M+H]⁺

Example 2519-Cyclopentyl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene251

1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withDCM (1:1) (8.45 mg, 0.0104 mmol), copper(I) iodide (3.94 mg, 0.0207mmol) and9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 (0.081 g, 0.21 mmol) were mixed in DMA (2.5 mL) andstirred under argon for 10 min and cyclopentylzinc bromide (0.5 M inTHF, 0.42 mL, 0.21 mmol) was transferred to this mixture via syringe.The reaction was carried out at 80° C. Subsequently cooled to room temp.and diluted with EtOAc and 1 N HCl and worked up. Purified via rp-HPLCto provide 251 (8 mg, 10% yield). LC/MS (ESI+): m/z 381 (M+H). ¹H NMR(400 MHz, DMSO) δ 8.27 (d, J=2.0, 1H), 8.08 (d, J=16.1, 1H), 7.16 (dd,J=8.2, 2.1, 1H), 6.98 (d, J=8.2, 1H), 5.83 (dt, J=13.2, 6.7, 1H), 4.34(t, J=5.0, 2H), 3.42 (t, J=5.0, 2H), 3.05 (p, J=8.3, 1H), 2.19-1.98 (m,2H), 1.73 (ddd, J=11.4, 6.9, 3.8, 4H), 1.61-1.48 (m, 8H).

Example 252(4-tert-Butyl-piperidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone252

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 4-tert-butylpiperidine to give 252. MS: (ESI+)=427.1

Example 2538-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid diethylamide 253

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and diethylamine to give 253. MS: (ESI+)=369.1

Example 2548-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid isobutyl-methyl-amide 254

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and N,2-dimethylpropan-1-amine to give 254. MS: (ESI+)=369.1

Example 2558-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid methyl-(3-methyl-butyl)-amide 255

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and N,3-dimethylbutan-1-amine to give 255. MS: (ESI+)=397.1

Example 2568-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (1,1-dioxo-tetrahydro-thiophen-3-yl)-methyl-amide 256

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and N-(1,1-dioxidotetrahydrothien-3-yl)-N-methylamine to give 256.MS: (ESI+)=445.1

Example 2578-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid methyl-(1-methyl-pyrrolidin-3-yl)-amide 257

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 1-methylpyrrolidin-3-amine to give 257. MS: (ESI+)=410.1

Example 2582-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol258

To a microwave vial was added8-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.300 g, 0.000650 mol) and potassium acetate (0.1915 g, 0.001951 mol)in acetonitrile (1 mL, 0.02 mol) and water (2 mL, 0.1 mol). The reactionwas thoroughly degassed and purged with N₂ for 5 minutes. A solution of1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(0.2724 g, 0.0008455 mol) in acetonitrile (1 mL, 0.02 mol) was added,followed by tetrakis(triphenylphosphine)palladium(0) (0.07515 g,6.504E-5 mol) and the vial was sealed immediately. The reaction washeated to 140° C. for 20 minutes in the microwave. The mixture wasdiluted with methylene chloride and filtered through celite. SaturatedNH₄Cl was added and the mixture was extracted 3 times with methylenechloride. The organic layers were combined, dried with MgSO₄ andconcentrated. The crude was dissolved in methylene chloride (7 mL, 0.1mol) and hydrogen chloride (4N in dioxoane, 0.38 mL, 0.001517 mol) wasadded dropwise. The reaction was stirred at room temperature for 1 hour.

The mixture was concentrated and partitioned between saturated sodiumbicarbonate and methylene chloride and extracted 3 times with methylenechloride. The organic phases were combined, dried with MgSO₄, andconcentrated. The crude was purified by reverse-phase HPLC to give 258(156.6 mg) as a solid. MS(ESI+) 493.1. ¹H NMR (400 MHz, DMSO) δ 8.42 (s,1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.89-7.83 (m, 1H), 7.76-7.65 (m, 1H),7.44-7.36 (m, 2H), 7.22 (d, J=1.5, 1H), 7.12 (dd, J=8.3, 1.6, 1H), 4.89(t, J=5.3, 1H), 4.33 (t, J=4.8, 2H), 4.15 (t, J=5.6, 2H), 3.76 (q,J=5.5, 2H), 3.41 (t, J=4.9, 2H)

Example 2592-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonyl-azetidin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene259

Following the procedure for 395,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenehydrochloride salt and methanesulfonyl chloride were reacted. Thereaction mixture was loaded directly onto a silica column with noaqueous work-up to give 259 isolated as a white solid (67 mg, 84%).LCMS: R_(T)=10.97 min, [M+H]⁺=446. ¹H NMR δ (ppm) (CDCl₃): 8.36 (1H, d,J=8.20 Hz), 7.90 (1H, d, J=0.68 Hz), 7.16 (1H, dd, J=8.24, 1.88 Hz),7.02 (1H, d, J=1.85 Hz), 5.93-5.83 (1H, m), 4.42-4.36 (2H, m), 4.30-4.22(2H, m), 4.10-4.03 (2H, m), 3.83-3.73 (1H, m), 3.43-3.37 (2H, m), 2.90(3H, s), 1.61 (6H, d, J=6.63 Hz)

Example 260(3-Methylamino-pyrrolidin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone260

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and N-methylpyrrolidin-3-amine to give 260. MS: (ESI+)=396.1

Example 261[1,4]Diazepan-1-yl-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone261

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 1,4-diazepane to give 261. MS: (ESI+)=382.1

Example 262Piperazin-1-yl-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone262

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and piperazine to give 262. MS: (ESI+)=382.1

Example 2631-[8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl]-piperidine-3-carboxylicacid 263

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and piperidine-3-carboxylic acid to give 263. MS: (ESI+)=396.1

Example 264(3-Methyl-piperazin-1-yl)-[8-(1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl]-methanone264

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 2-methylpiperazine to give 264. MS: (ESI+)=396.1

Example 2652-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(2-trifluoromethyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene265

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 2-(trifluoromethyl)pyridin-3-ylboronic acid werereacted to give 265 (0.058 g, 25%). ¹H NMR (400 MHz, DMSO) δ 9.30 (d,J=2.2, 1H), 8.28 (d, J=8.0, 1H), 8.19 (t, J=7.9, 1H), 8.12 (s, 1H), 8.04(dd, J=8.5, 2.3, 1H), 7.82 (t, J=17.9, 1H), 7.23 (d, J=8.5, 1H), 5.93(dt, J=13.2, 6.7, 1H), 4.45 (t, J=4.9, 2H), 3.50 (t, J=4.8, 2H), 1.57(d, J=6.6, 6H). MS (ESI(+)): m/z 458.1 (M+H)

Example 2662-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(4-methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene266

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 4-methoxypyridin-3-ylboronic acid were reacted togive 266 (0.045 g, 28%). ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=2.1, 1H),8.50 (d, J=6.0, 2H), 7.92 (s, 1H), 7.46 (dd, J=8.3, 2.2, 1H), 7.15 (d,J=8.4, 1H), 6.93 (d, J=5.7, 1H), 5.84 (dt, J=13.3, 6.6, 1H), 4.46 (t,J=5.0, 2H), 3.91 (s, 3H), 3.45 (t, J=5.0, 2H), 1.59 (d, J=6.7, 6H). MS(ESI(+)): m/z 420.1 (M+H)

Example 2678-(6-Morpholin-4-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxyethyl)-isopropylamide 267

To a microwave vial was added8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxyethyl)-isopropylamide (0.100 grams, 0.243 mmol) in 2M sodiumcarbonate (0.500 mL) and ACN (0.636 mL), and then4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethyl)morpholine(0.292 mmol) was added. This solution was degassed by bubbling nitrogenthrough the solution for several minutes. Finally, palladiumtetrakis(triphenylphosphine)palladium(0) was added and the vial wastightly capped. The reaction mixture was then flash heated on a Biotagemicrowave at 140° C. for 20 minutes. The cooled reaction mixture wasdiluted with EtOAc and the organic was washed with water, then salineand dried (Na2SO4) before concentration to a solid. The crude materialwas purified by preparative RP-HPLC to give 267. MS: (ESI+)=495.1

Example 2688-(1-Methyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 268

Following Example 267,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxyethyl)-isopropylamide and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere reacted to give 268. MS: (ESI+)=413.1

Example 2698-[1-(2-Morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 269

Following Example 267,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxyethyl)-isopropylamide and4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholinewere reacted to give 269. MS: (ESI+)=512.2

Example 2708-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 270

Following Example 267,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxyethyl)-isopropylamide and2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineto give 270. MS: (ESI+)=509.2

Example 2712-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(2-methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene271

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),2-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (282mg, 1.2 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10 mmol)and CH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube, and themixture was heated by microwave at 120° C. for 20 min under N₂. Thereaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to give 271 (270 mg, yield: 46%). ¹HNMR (DMSO-d₆, 400MHz): δ8.30-8.26 (m, 2H), 8.15 (d, J=6.8 Hz, 1H), 7.94 (d, J=8.4 Hz,2H), 7.92 (t, J=9.2 Hz, 1H), 7.29-7.18 (m, 2H), 4.33 (s, 2H), 3.96 (s,3H), 3.16 (s, 2H). ESI-MS: m/z=490 [M+H⁺]

Example 2724-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2-methyl-butan-2-ol272

Following the procedures for 246,4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2-methyl-but-3-yn-2-olwas prepared (Yield: 69%. ¹H NMR (DMSO-d₆, 400 MHz): δ8.30 (s, 1H),7.93-7.877 (m, 1H), 7.74-7.68 (m, 1H), 7.43-7.37 (m, 2H), 7.29 (d, J=8.4Hz, 1H), 6.99 (s, 1H), 5.60 (s, 1H), 4.30 (t, J=4.4 Hz, 2H), 3.12 (t,J=4.4 Hz, 2H), 1.21 (s, 6H). ESI-MS: (m/z)=465 [M+H]⁺) from9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azuleneand 2-methylbut-3-yn-2-ol, and hydrogenated to give 272 Yield: 37%. ¹HNMR (DMSO-d₆, 400 MHz): δ8.26 (s, 1H), 7.90-7.84 (m, 1H), 7.69-7.63 (m,1H), 7.39-7.34 (m, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.06-7.03 (m, 2H), 4.22(t, J=4.8 Hz, 2H), 3.08 (t, J=4.8 Hz, 2H), 2.68-2.63 (m, 2H), 1.69-1.64(m, 2H), 1.10 (s, 6H). LC-MS (ESI): m/z=469[M+H]⁺

Example 273(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-(2-morpholin-4-yl-ethyl)-amine273

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),(2-Morpholin-4-yl-ethyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine(400 mg, 1.2 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10mmol) and CH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube,and the mixture was heated by microwave at 120° C. for 20 min under N₂.The reaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to give 273 (97.5 mg, yield: 17%). ¹HNMR (DMSO-d₆, 400MHz): δ8.61 (s, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.91-7.87 (m, 2H),7.67-7.67 (m, 2H), 7.37-7.35 (m, 2H), 7.16 (s, 2H), 7.21 (s, 1H), 6.85(s, 1H), 6.60 (d, J=8.8 Hz, 2H), 4.27 (s, 2H), 3.28 (s, 6H), 3.32 (s,4H), 3.11 (s, 4H). ESI-MS: m/z=588 [M+H⁺]

Example 274(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-(2-methanesulfonyl-ethyl)-amine274

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(470 mg, 1.0 mmol), from the procedure for 249,2-Methanesulfonylethylamine (147, 1.2 mmol), DIPEA (340 mg, 3 mmol) andNMP (4 mL) were added in a 10 mL of sealed tube, and the mixture washeated by microwave at 150° C. for 120 min under N₂. The reactionmixture was filtered to gather the solution and water was added. Themixture was extracted by DCM (20 mL×3). The combined organic layers weredried over Na₂SO₄, concentrated in vacuo, and purified by preparativeHPLC to give 274 (23.7 mg, yield: 4.1%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.77(s, 1H), 8.38 (s, 1H), 8.04-8.00 (m, 2H), 7.84-7.77 (m, 2H), 7.29 (s,2H), 6.77 (d, J=8.8 Hz, 1H), 4.37 (s, 2H), 3.88-3.81 (m, 2H), 3.50-3.47(m, 2H), 3.23-3.21 (m, 2H), 3.10 (s, 3H). ESI-MS: m/z=581 [M+H⁺]

Example 275{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(2-methoxy-ethyl)-amine275

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol), 2-Methoxy-ethylamine(147 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg,1.44 mmol) in dioxane (2 mL) was bubbled N₂ for 10 min and then stirredat 120° C. for 2.5 min under the irradition of microwave. The mixturewas filtered over ceilite. The filtrate was concentrated to dryness andpurified by pre-HPLC to afford 110 mg of 275. (yield=34%). ¹H NMR(CDCl₃, 400 MHz): δ8.10 (s, 1H), 7.61-7.54 (m, 1H), 7.14-7.06 (m, 4H),6.30 (d, J=8.8 Hz, 1H), 4.62-4.58 (m, 1H), 4.25-4.24 (m, 2H), 3.60-3.58(m, 2H), 3.52-3.48 (m, 2H), 3.41 (s, 3H), 3.13-3.10 (m, 2H). LC-MS(ESI): m/z=456 [M+H]⁺

Example 276{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-isopropyl-amine276

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol), isopropylamine (80 mg,1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44mmol) in dioxane (2 mL) was bubbled N₂ for 10 min and then stirred at120° C. for 5 min under the irradition of microwave. The mixture wasfiltered over celite. The filtrate was concentrated to dryness andpurified by pre-HPLC to afford 80 mg of 276 (yield=25%). ¹H NMR (CDCl₃,400 MHz) δ: 8.01 (s, 1H), 7.50-7.44 (m, 1H), 7.18-7.15 (m, 1H),7.09-6.99 (m, 3H), 6.13 (d, J=8.8 Hz, 1H), 4.19-4.14 (m, 2H), 3.96-3.80(m, 2H), 3.45-3.41 (m, 1H), 3.06-3.04 (m, 2H), 3.18-3.12 (m, 6H). LC-MS(ESI): m/z=439 [M+H]⁺

Example 2779-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 277

9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (57 mg, 0.138 mmol),1-(2-(tetrahydro-2H-pyran-2yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(67 mg, 0.208 mmol), Tetrakis(triphenylphosphine)palladium(0) (16 mg,0.0138 mmol), 1.5 mL 1 M potassium acetate in water, and 1.5 mLacetonitrile were combined in a microwave vial and placed on the CEMmicrowave for 20 minutes at 140° C. Complete reaction by LCMS. Dilutedreaction with 2 M HCl and extracted product with ethyl acetate. Some ofthe THP group fell off during work-up. The final Intermediate was in theethyl acetate layer, which was dried over magnesium sulfate andconcentrated in vacuo. Flash purified 0 to 10% MeOH in dichloromethaneand again concentrated in vacuo. The THP intermediate was deprotectedwith 1 M HCl in dioxane (5 mL0 over 72 hours). Complete deprotection byLCMS. Concentrated in vacuo and purified by HPLC to give 277 (3.8 mg, 6%yield, M+1 443.1)

Example 2789-(2-Amino-4-methyl-pyrimidin-5-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 278

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (52.2 mg, 0.127 mmol) and4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(35.8 mg, 0.152 mmol) were reacted to give 278 (0.6 mg, 1% yield M+1440.1)

Example 2799-(6-Amino-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 279

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (52.5 mg, 0.128 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (33.7 mg,0.153 mmol) were reacted to give 279 (7.2 mg, 13% yield, M+1 425.1).

Example 2809-(4-Methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 280

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (52.3 mg, 0.127 mmol) and4-methylpyridin-3-ylboronic acid (21.0 mg, 0.153 mmol) were reacted togive 280 (4.3 mg, 8% yield, M+1 424.1).

Example 2819-(2-Amino-pyrimidin-5-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 281

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (53.4 mg, 0.130 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (34.4mg, 0.156 mmol) were reacted to give 281 (6.6 mg, 12% yield, M+1 426.1)

Example 2829-(6-Methylamino-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 282

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (52.9 mg, 0.129 mmol) and tert-butylmethyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)carbamate(51.6 mg, 0.154 mmol) were reacted to give 282, purified by HPLC (1.4mg, 2.5% yield, M+1 439.1).

Example 2839-(2-Ethoxy-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene283

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 2-ethoxypyridin-3-ylboronic acid were reacted to give283 (0.045 g, 27%). ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J=2.2, 1H), 8.15(dd, J=4.9, 1.8, 1H), 7.92 (s, 1H), 7.65 (dd, J=7.3, 1.8, 1H), 7.55 (dt,J=11.2, 5.6, 1H), 7.13 (d, J=8.4, 1H), 7.02-6.93 (m, 1H), 5.84 (dt,J=13.2, 6.6, 1H), 4.55-4.39 (m, 4H), 3.45 (t, J=5.0, 2H), 1.59 (d,J=6.6, 6H), 1.38 (t, J=7.0, 3H). MS (ESI(+)): m/z 434.1 (M+H)

Example 284[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-isoxazol-3-yl-amine284

Following the procedure for 119,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehydeand 3-amino-isoxazole were reacted. Purification by flash chromatography(SiO₂, 0-20% EtOAc in DCM) gave 284 as a white solid (154 mg, 52%).LCMS: R_(T)=10.79 min, [M+H]⁺=409. ¹H NMR δ (ppm) (CDCl₃): 8.33 (1H, d,J=8.10 Hz), 8.04 (1H, d, J=1.68 Hz), 7.90 (1H, s), 7.16 (1H, d, J=8.19Hz), 7.06 (1H, s), 5.93-5.84 (1H, m), 5.85-5.83 (1H, m), 4.42 (2H, s),4.38 (2H, t, J=5.02 Hz), 3.42-3.36 (2H, m), 1.60 (6H, d, J=6.62 Hz). 1Exchangeable proton not seen.

Example 2852-{[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-amino}-ethanol285

Following the procedure for 212,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehydeand ethanolamine were reacted to give 285 isolated as a pale yellowsolid (131 mg, 47%). LCMS: R_(T)=6.85 min, [M+H]⁺=386. ¹H NMR δ (ppm)(CDCl₃): 8.31 (1H, d, J=8.11 Hz), 7.89 (1H, s), 7.12 (1H, d, J=8.19 Hz),7.02 (1H, s), 5.93-5.82 (1H, m), 4.37 (2H, t, J=5.06 Hz), 3.81 (2H, s),3.66 (2H, t, J=5.12 Hz), 3.38 (2H, t, J=5.06 Hz), 2.81 (2H, t, J=5.11Hz), 1.60 (6H, d, J=6.63 Hz). 2 Exchangeable protons not seen.

Example 2861-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethane-1,2-diol286

A solution of2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-vinyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(1.28 mmol) in acetone, THF and water (15 mL, 1:1:1) was treated withN-methylmorpholine-N-oxide (299 mg, 2.56 mmol) then potassium osmatedihydrate (14 mg, 0.04 mmol). The reaction mixture was stirred at roomtemperature overnight. Solid sodium sulfite was added and the reactionmixture was extracted with EtOAc. The combined organics were dried oversodium sulfate, concentrated and the residue purified by reverse phaseHPLC to give 286 as a colorless solid (222 mg, 46%). LCMS: 373.1. ¹H NMR(400 MHz, DMSO) δ 8.28 (d, J=8.2 Hz, 1H), 8.09 (s, 1H), 7.16 (d, J=8.1Hz, 1H), 7.04 (s, 1H), 5.82 (dt, J=13.3, 6.5 Hz, 1H), 5.26 (d, J=4.4 Hz,1H), 4.70 (t, J=5.8 Hz, 1H), 4.54 (dd, J=10.4, 5.6 Hz, 1H), 4.36 (t,J=5.0 Hz, 2H), 3.53-3.35 (m, 4H), 1.55 (d, J=6.6 Hz, 6H)

Example 2872-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol287

Similarly to as described in General Procedure C:8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranylether was accomplished by adding 2N HCl to the crude reaction mixture.Purification by reverse phase HPLC gave 287 as a colorless solid (53mg). LCMS: 437.1.

Example 2882-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-isobutyramide288

Following the procedure for 240,2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionicacid was reacted with ammonium chloride to give 288. MS(ESI+) 504.1. ¹HNMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.3-8.25 (m, 2H), 8.04 (s, 1H), 7.51(dd, J=8.3, 1.5, 1H), 7.40 (d, J=1.4, 1H), 7.16 (br, 1H), 6.77 (br, 1H),5.86 (q, J=8.7, 2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 1.74 (s,6H)

Example 2898-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid cyclopentyl-(2-hydroxy-ethyl)-amide 289

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 2-(cyclopentylamino)ethanol to give 289. MS: (ESI+)=425.1

Example 2908-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (3-hydroxy-propyl)-isopropyl-amide 290

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and 3-(isopropylamino)propan-1-ol to give 290. MS: (ESI+)=413.1

Example 2918-(3,5-Dimethyl-isoxazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 291

Following Example 267,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxyethyl)-isopropylamide and3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole togive 291. MS: (ESI+)=428.1

Example 2921-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-ethanol292

To a solution of1-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-ethanone(0.2357 g, 0.0005976 mol) in ethanol (2.5 mL, 0.043 mol) was addedsodium tetrahydroborate (0.02713 g, 0.0007172 mol). The reaction wasstirred at room temperature for 5 hours. The reaction was quenched with2N HCl and diluted with water. Ethyl acetate was added and the aqueouslayer was extracted 3× with ethyl acetate. The organic phases werecombined, dried with MgSO₄, and concentrated. The crude was purified byreverse-phase HPLC to give 292 (74.8 mg) as a white solid. MS(ESI+)397.0. ¹H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.25 (d, J=8.2, 1H), 7.16(dd, J=8.2, 1.1, 1H), 7.05 (m, 1H), 5.85 (q, J=8.7, 2H), 5.19 (d, J=4.4,1H), 4.79-4.63 (m, 1H), 4.36 (t, J=5.0, 2H), 3.45 (t, J=5.0, 2H), 1.34(d, J=6.4, 3H)

Example 2931-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-propan-2-ol293

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol),2-Trimethylsilanyloxy-propylamine (211 mg, 1.44 mmol), X-phos (70 mg,0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 125° C. for 7 min under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-TLC(EtOAc/hexanes=2:1) to afford 110 mg of 293. (yield=34%). ¹H NMR (CDCl₃,400 MHz): δ8.01 (s, 1H), 7.50-7.45 (m, 1H), 7.06-6.98 (m, 4H), 6.23 (d,J=8.8 Hz, 1H), 4.54-4.50 (m, 1H), 4.17-4.15 (m, 2H), 3.98-3.94 (m, 1H),3.44-3.40 (m, 1H), 3.15-3.00 (m, 3H), 1.21-1.17 (m, 3H). LC-MS (ESI):m/z=456 [M+H]⁺

Example 2942-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-pyrrolidin-1-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene294

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene,from the procedure for 249, (470 mg, 1.0 mmol), Pyrrolidine (85 mg, 1.2mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL ofsealed tube, and the mixture was heated by microwave at 150° C. for 120min under N₂. The reaction mixture was filtered to gather the solutionand water was added. The mixture was extracted by DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, concentrated in vacuo,and purified by preparative HPLC to give 294 (31.3 mg, yield: 5.9%).¹HNMR (DMSO-d₆, 400 MHz): δ8.81 (s, 1H), 8.38 (s, 1H), 8.12 (d, J=8.8Hz, 1H), 7.98-7.97 (m, 1H), 7.78-7.77 (m, 1H), 7.76-7.78 (m, 2H),7.46-7.40 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.48(t, J=4.4 Hz, 1H), 7.26 (s, 1H), 6.60 (d, J=8.8 Hz, 1H), 4.38 (s, 2H),3.54 (s, 3H), 3.22 (s, 2H), 2.07 (s, 4H). ESI-MS: m/z=529 [M+H⁺]

Example 2955-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-ol295

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),5-(4,4,5-Trimethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ol (268 mg, 1.2mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10 mmol) andCH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube, and themixture was heated by microwave at 120° C. for 20 min under N₂. Thereaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to give 295 (34.7 mg, yield: 7.1%). ¹HNMR (DMSO-d₆, 400MHz): δ8.30 (s, 1H), 8.10 (s, 1H), 7.98-7.92 (m, 2H), 7.78 (t, J=4.8 Hz,1H), 7.67 (d, J=8.8 Hz, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.20 (s, 1H), 6.43(d, J=8.8 Hz, 1H), 4.29 (s, 2H), 3.14 (s, 2H), ESI-MS: m/z=475 [M+H⁺]

Example 296N′-(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-N,N-dimethyl-ethane-1,2-diamine296

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(470 mg, 1.0 mmol), from the procedure for 249,2-(N,N-Dimethyl)-ethylamine (90 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol)and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture washeated by microwave at 150° C. for 120 min under N₂. The reactionmixture was filtered to gather the solution and water was added. Themixture was extracted by DCM (20 mL×3). The combined organic layers weredried over Na₂SO₄, concentrated in vacuo, and purified by preparativeHPLC to give 296 (69 mg, yield: 13%). ¹HNMR (DMSO-d₆, 400 MHz): δ9.50(s, 1H), 8.72 (s, 1H), 8.31 (s, 1H), 7.97-7.91 (m, 2H), 7.77-7.72 (m,2H), 7.48-7.43 (m, 2H), 7.15 (s, 1H), 6.99 (s, 1H), 6.72 (d, J=4.4 Hz,1H), 4.31 (s, 2H), 3.86 (s, 2H), 3.33 (s, 2H), 3.33 (s, 2H), 3.15 (s,2H), 2.75 (s, 6H). ESI-MS: m/z=546 [M+H⁺]

Example 2972-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylicacid oxetan-3-ylamide 297

Similarly to as described in General Procedure D,2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylicacid was reacted with 3-aminooxetane hydrochloride to give 297 as acolorless solid after reverse phase HPLC (146 mg). LCMS: 496.1

Example 2989-(2-Methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 298

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (53.4 mg, 0.130 mmol) and2-methylpyridin-3-ylboronic acid (21.3 mg, 0.156 mmol) were reacted togive 298 (9.2 mg, 17% yield, M+1 424.1)

Example 2999-(2-Methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 299

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (52.2 mg, 0.127 mmol) and2-methoxypyridin-3-ylboronic acid (23.3 mg, 0.152 mmol) were reacted togive 299 (4.0 mg, 7% yield, M+1 440.1).

Example 3008-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide 300

Following Example 216, to a well stirred solution of8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid and (S)-3-amino-5-methylhexan-1-ol to give 300. MS: (ESI+)=413.1

Example 3019-(1-Benzenesulfonyl-1H-pyrazol-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene301

9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere reacted under palladium Suzuki conditions to give 301 (39% yield).LC/MS (ESI+): m/z 519 (M+H). ¹H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.62(d, J=2.1, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 8.03 (d, J=7.6, 2H), 7.81(t, J=7.5, 1H), 7.75-7.60 (m, 3H), 7.12 (d, J=8.4, 1H), 5.82 (dt,J=13.0, 6.6, 1H), 4.39 (t, J=4.8, 2H), 3.46 (t, J=4.9, 2H), 1.59 (d,J=6.6, 6H)

Example 3022-{4-[2-(2-Pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol302

Similarly to as described in General Procedure C:8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate.The crude ester was reduced with lithium aluminum hydride as describedfor2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol.The product was purified by HPLC to give 302 as a colorless solid (32mg). LCMS: 472.1.

Example 3032-(4-{2-[2-(1-Methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol303

Similarly to as described in General Procedure C:8-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate.The crude ester was reduced with lithium aluminum hydride as describedfor2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol.The product was purified by HPLC to give 303 as a colorless solid (27mg). LCMS: 478.2.

Example 3042-(1-Isopropyl-1H-imidazol-2-yl)-9-(2-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene304

To a solution of9-Chloro-2-(1-isopropyl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(63 mg, 0.18 mmol), Potassium acetate (60.2 mg, 0.613 mmol),2-methylpyridine-3-boronic acid, (32.2 mg, 0.235 mmol) andTetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) inAcetonitrile (2 mL, 30 mmol) and Water (2 mL, 100 mmol) was degassed.The reaction was heated in the microwave at 140° C. for 20 minutes. Thereaction was cooled to r.t., then extract with ethyl acetate. Thecombined organics were concentrated and purified by reverse phase HPLCto give 304. MS: (ESI+)=403.1. ¹H NMR (400 MHz, DMSO) δ 8.55-8.47 (m,1H), 7.86 (d, J=7.7 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.50-7.43 (m, 2H),7.36 (dd, J=7.7, 4.9 Hz, 1H), 7.29 (s, 1H), 7.00 (s, 1H), 4.82 (dt,J=13.3, 6.5 Hz, 1H), 4.43 (t, J=4.6 Hz, 2H), 2.65 (s, 3H), 1.44 (d,J=6.6 Hz, 6H).

Example 3052-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(6-methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene305

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 6-methoxypyridin-3-ylboronic acid were reacted togive 305 (0.027 g, 17%). ¹H NMR (400 MHz, DMSO) δ 8.62 (d, J=2.3, 1H),8.48 (d, J=2.0, 1H), 8.11 (s, 1H), 7.99 (dd, J=8.6, 2.5, 1H), 7.60 (dd,J=8.4, 2.3, 1H), 7.18 (d, J=8.4, 1H), 6.96 (d, J=8.6, 1H), 5.77 (dt,J=13.3, 6.8, 1H), 4.42 (t, J=4.9, 2H), 3.91 (s, 3H), 3.48 (t, J=4.8,2H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)

Example 3069-(2-Fluoro-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene306

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 2-fluoropyridin-3-ylboronic acid were reacted to give306. MS (ESI(+)): m/z 408.1 (M+H).

Example 307 4,5-Dihydro-6-oxa-1-thia-benzo[e]azulene-2,8-dicarboxylicacid2-{[2-chloro-5-(4-methyl-piperazine-1-carbonyl)-phenyl]-methyl-amide}8-methylamide307

A solution of8-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (25g, 0.077 mol) in 200 mL of SOCl₂ was heated at 80° C. for 3 h.Concentration gave the crude acid chloride. A suspension of the crudeacid chloride (ca. 0.077 mol) from above in 1000 mL of THF at 0° C. wastreated with a solution of 3-amino-4-chloro-benzoic acid methyl ester(15.7 g, 1.1 eq)/pyridine (30 mL) in 100 mL of THF. The mixture wasallowed to reach room temperature overnight. The reaction solution wasconcentrated to 1/2 volume, diluted with water. The resultingprecipitate was filtered, washed with water and Et₂O. The filter cakewas dried to a constant weight under vacuum to give methyl3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate(32.9 g, yield 87%). LC-MS: (ESI, m/z)=494 [M+1]⁺

To a solution of methyl3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate(32 g, 65 mmol) and Cs₂CO₃ (42.4 g, 130 mmol) in DMF (500 mL) was addedCH₃I (12 mL, 195 mmol). The reaction mixture was stirred at roomtemperature overnight. Then it was concentrated to remove the DMF, andwater was added into the mixture. The resulting precipitate wasfiltrated, washed by water, and dried to give methyl3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate(31 g, 94%)¹H NMR (CDCl₃, 400 MHz): δ8.07-7.08 (m, 6H, ArH), 6.81 (s,1H, ═CH), 4.22 (t, J=5.2 Hz, 2H, CH₂), 3.94 (s, 3H, OCH₃), 3.40 (s, 3H,NCH₃), 3.01 (t, J=5.2 Hz, 2H, CH₂)

To a suspension of methyl3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate(31 g, 61 mmol) in THF (200 mL) and H₂O (100 mL) was added LiOH.H₂O(6.42 g, 153 mmol). The reaction mixture was stirred at room temperatureovernight. Then it was acidified with 2N HCl to pH 2-3, and concentratedto remove most of solvent. The resulting precipitate was washed bywater, dried to give the carboxylic acid,3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (27.3 g, 91%). LC-MS: (ESI, m/z)=494 [M+1]⁺

To a mixture of 1-methyl-piperazine (1.22 g, 12.18 mmol), DIPEA (3 mL),HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (3.0 g, 6.09 mmol) under nitrogen atmosphere at room temperature.The reaction mixture was stirred overnight, diluted with water,extracted with EtOAc. The organic layer was dried over Na₂SO₄,concentrated in vacuo to give8-bromo-N-(2-chloro-5-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(3.3 g, yield 94%)¹H NMR (DMSO-d6, 400 MHz): δ7.74-7.21 (m, 6H, ArH),6.67 (s, 1H, ═CH), 4.18 (t, J=4.4 Hz, 2H, CH₂), 3.31-2.12 (m, 16H, CH₃,CH₂)

A suspension of8-bromo-N-(2-chloro-5-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(500 mg, 0.87 mmol), Pd(OAc)₂ (10 mg, 0.0435 mmol), Xantphos (50 mg,0.087 mmol), MeNH₂.HCl (88 mg, 1.30 mmol) and Na₂CO₃ (277 mg, 2.61 mmol)in toluene (10 mL) was heated at 80° C. under atmosphere of CO fromballoon for overnight, filtrated and concentrated. The crude product waspurified by flash column chromatography on silica gel(DCM/MeOH=40:1-20:1 as eluted solvent) to give 307 (148.6 mg, yield31%). ¹H NMR (CDCl₃, 400 MHz): δ7.60-6.94 (m, 7H, NH, ArH), 6.23 (s, 1H,═CH), 4.23 (t, J=4.8 Hz, 2H, CH₂), 3.79-2.09 (m, 19H, CH₃, CH₂). LC-MS:(ESI, m/z)=553 [M+1]⁺

Example 308 4,5-Dihydro-6-oxa-1-thia-benzo[e]azulene-2,8-dicarboxylicacid2-{[2-chloro-5-(4-methyl-piperazine-1-carbonyl)-phenyl]-methyl-amide}8-[(2-methanesulfonyl-ethyl)-amide] 308

A suspension of8-bromo-N-(2-chloro-5-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(500 mg, 0.87 mmol), Pd(OAc)₂ (10 mg, 0.0435 mmol), Xantphos (50 mg,0.087 mmol), MeSO₂(CH₂)₂NH₂.HCl (207 mg, 1.30 mmol) and Na₂CO₃ (277 mg,2.61 mmol) in toluene (10 mL) was heated at 80° C. under atmosphere ofCO from balloon for overnight. The mixture was filtered, concentrated,and the crude product purified by flash column chromatography on silicagel (DCM/MeOH=40:1-20:1 as eluted solvent) to give 308 (289.2 mg, yield52%). ¹HNMR(CDCl₃, 400 MHz): δ 7.60-6.97 (m, 8H, ArH), 4.23 (t, J=4.8Hz, 2H, CH₂), 4.01-2.17 (m, 23H, CH₃, CH₂). LC-MS: (ESI, m/z)=645 [M+1]⁺

Example 3092-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene309

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd(OAc)₂ (20 mg, 0.1 mmol),1-(2,2,2-Trifluoro-ethyl)-piperazine (175 mg, 1.44 mmol), X-phos (70 mg,0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) wasbubbled N₂ for 10 min and then stirred at 125° C. for 9 min under theirradition of microwave. The mixture was filtered over ceilite. Thefiltrate was concentrated to dryness and purified by pre-HPLC to afford110 mg of 309. (yield=28%). ¹H NMR (CDCl₃, 400 MHz): δ8.08 (s, 1H),7.57-7.51 (m, 1H), 7.16-7.06 (m, 4H), 6.52 (d, J=8.8 Hz, 1H), 4.25-4.23(m, 2H), 3.47-3.44 (m, 4H), 3.12-3.02 (m, 4H), 2.80-2.77 (m, 4H). LC-MS(ESI): m/z=549 [M+H]⁺

Example 3109-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene310

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol), Pd(OAc)₂ (22.4 mg, 0.1 mmol),2,5-Diaza-bicyclo[2.2.1]heptane (120 mg, 1.2 mmol), X-phos (47 mg, 0.10mmol), tert-butoxide (200 mg, 20 mmol) in dioxane (2 mL) was bubbled N₂for 10 min and then stirred at 120° C. for 6 min under the irradition ofmicrowave. The mixture was filtered over ceilite. The filtrate wasconcentrated to dryness and purified by pre-HPLC to afford 310. (61.4mg, yield=13%). ¹H NMR (CDCl₃, 400 MHz): δ 8.27 (s, 1H), 7.89-7.88 (m,1H), 7.72-7.99 (m, 1H), 7.41-7.39 (m, 1H), 7.28-7.16 (m, 2H), 6.39 (d,J=8.8 Hz, 1H), 4.41 (s, 1H), 4.16 (s, 2H), 3.46-3.41 (m, 6H), 2.74 (s,2H), 1.06 (t, J=6.8 Hz, 2H). LC-MS (ESI): m/z=479 [M+H]⁺

Example 3111-(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone311

Compound 310 (479 mg, 1.0 mmol), Acetyl chloride (100 mg, 1.2 mmol),DIPEA (260 mg, 2.0 mmol) was dissolved in THF (10 mL). The reactionmixture was stirred at r.t. for 1 hour. LC-MS indicated the reaction wascompleted. To the reaction mixture was added 20 mL of water, the mixturewas extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate, and concentrated to dryness. The crude waspurified by pre-HPLC to afford 311 (78.1 mg, yield: 15%). ¹HNMR(DMSO-d₆, 400 MHz): δ8.27 (s, 1H), 7.91-7.90 (m, 1H), 7.74 (s, 1H),7.43-7.39 (m, 1H), 7.23-7.20 (m, 2H), 6.48 (t, J=4.4 Hz, 1H), 4.77 (s,2H), 3.53 (s, 2H), 3.53-3.32 (m, 4H), 3.19 (s, 2H), 1.96 (s, 3H), 1.23(s, 2H). ESI-MS: m/z=521 [M+H⁺]

Example 3121-((2R,6S)-4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2,6-dimethyl-piperazin-1-yl)-ethanone312

To a mixture of2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(150 mg, 0.3 mmol), potassium carbonate (84 mg, 0.6 mmol) in DMF (5 mL)was added acetic anhydride (0.3 mL) at −15° C. The mixture was slowlywarmed to room temperature and stirred for 30 min. The reaction mixturewas added 30 mL of water. The solid was collected to give 100 mg of 312.Yield=62%. ¹H NMR (CDCl₃, 400 MHz): δ8.03 (s, 1H), 7.51-7.46 (m, 1H),7.19-7.00 (m, 4H), 6.50 (d, J=8.8 Hz, 1H), 4.19 (t, J=4.4 Hz, 2H),3.66-3.65 (m, 2H), 3.07 (t, J=4.8 Hz, 2H), 0.93-2.89 (m, 2H), 2.13 (s,3H), 2.03 (s, 2H), 1.29-1.24 (m, 6H). ESI-MS: m/z=537 [M+H⁺]

Example 3132-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene313

To a mixture of2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(100 mg, 0.2 mmol), Cesium carbonate (131 mg, 0.4 mmol) inN,N-dimethylformamide (5 mL) was added CH₃I (0.025 mL, 0.4 mmol) at −15°C. The mixture was slowly warmed to room temperature and stirred forabout 30 min. The reaction mixture was added 30 mL of water. The solidwas collected to give 70 mg of 313. Yield=60%. ¹H NMR (CDCl₃, 400 MHz):δ8.02 (s, 1H), 7.51-7.46 (m, 1H), 7.11-6.97 (m, 4H), 6.46 (d, J=8.8 Hz,1H), 4.18 (t, J=4.8 Hz, 2H), 3.85 (d, J=13.6 Hz, 2H), 3.08 (t, J=4.8 Hz,2H), 2.59 (t, J=7.2 Hz, 2H), 2.26-2.19 (m, 4H), 1.14 (d, J=6.8 Hz, 6H).ESI-MS: m/z=509 [M+H⁺]

Example 3142-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-4-ethyl-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene314

A mixture of2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(150 mg, 0.3 mmol), 1-Bromo-2-fluoro-ethane (65 mg, 0.45 mmol) andCesium carbonate (200 mg, 0.6 mmol) in N,N-Dimethyl-formamide (2 mL) wasstirred at 120° C. for 1 h under the irradiation of microwave. Thereaction mixture was filtered over celite and purified by pre-TLC(Hexanes/EtOAc=1:1) to afford 314 Yield=56%. ¹H NMR (CDCl₃, 400 MHz):δ8.02 (s, 1H), 7.49-7.46 (m, 1H), 7.11-6.97 (m, 4H), 6.45 (d, J=8.8 Hz,1H), 4.18 (t, J=4.8 Hz, 2H), 3.86 (d, J=11.6 Hz, 2H), 3.07 (t, J=4.8 Hz,2H), 2.96 (q, J₁=7.2 Hz, J₂=5.2 Hz, 2H), 2.64-2.51 (m, 4H), 1.13 (d,J=6.0 Hz, 6H), 0.88-0.81 (m, 3H). ESI-MS: m/z=523 [M+H⁺]

Example 3152-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[(3R,5S)-4-(2-fluoro-ethyl)-3,5-dimethyl-piperazin-1-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene315

A mixture of2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(150 mg, 0.3 mmol), 1-Bromo-2-fluoro-ethane (65 mg, 0.45 mmol) andCesium carbonate (200 mg, 0.6 mmol) in N,N-Dimethyl-formamide (2 mL) wasstirred at 120° C. for 1 h under the irradiation of microwave. Thereaction mixture was filtered over celite and purified by pre-TLC(Hexanes/EtOAc=1:1) to afford 45 mg of 315 (yield: 28%). ¹H NMR (CDCl₃,400 MHz): δ8.23 (s, 1H), 7.51-7.46 (m, 1H), 7.10-6.93 (m, 4H), 6.46 (d,J=8.8 Hz, 1H), 4.52 (t, J=5.6 Hz, 2H), 4.40 (t, J=5.6 Hz, 2H), 4.18 (t,J=4.8 Hz, 2H), 3.85-3.82 (m, 2H), 3.07-2.94 (m, 4H), 2.70 (d, J=6.0 Hz,2H), 2.55-2.49 (m, 2H), 1.22-1.34 (d, J=6.0 Hz, 6H). LC-MS (ESI):m/z=541 [M+H]⁺

Example 3161-((2R,6S)-4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2,6-dimethyl-piperazin-1-yl)-2,2,2,-trifluoro-ethanone316

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), (2S,6R)-2,6-dimethylpiperazine (164 mg, 1.44 mmol),^(t)BuONa (47 mg, 0.48 mmol), Pd(OAc)₂ (49 mg, 0.3 mmol) and2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg,0.29 mmol), in dioxane (2 mL) was bubbled N₂ for 10 min and then stirredat 120° C. for 1 h under the irradition of microwave. The mixture wasfiltered by celite. The filtrate was concentrated to dryness andpurified by pre-TLC(EtOAc) to afford 220 mg of2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene.(Yield: 62%)¹H NMR (DMSO, 400 MHz): δ8.28 (s, 1H), 8.22 (s, 1H),7.94-7.88 (m, 1H), 7.72-7.67 (m, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.24 (t,J=2.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.20 (t, J=4.4 Hz, 2H), 3.99 (q,J=2.4, 12.8 Hz, 2H), 3.12 (t, J=4.8 Hz, 2H), 2.87-2.82 (m, 2H), 1.10 (d,J=6.0 Hz, 6H). LC-MS (ESI): m/z=495 [M+H]⁺

A mixture of2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(150 mg, 0.3 mmol), potassium carbonate (84 mg, 0.6 mmol) was suspendedin N,N-dimethylformamide (5 mL). The mixture was stirred at −15° C. for10 min and added 2,2,2-trifluoroacetic anhydride dropwise. The mixturewas slowly warmed to room temperature and stirred for about 30 min. Thereaction mixture was added 30 ml of water. The solid was collected toget 142 mg of 316. (HPLC purity: 95%)¹H NMR (CDCl₃, 400 MHz): δ8.04 (s,1H), 7.52-7.47 (m, 1H), 7.19-7.00 (m, 4H), 6.50 (m, J=8.8 Hz, 1H), 4.62(s, 1H), 4.23-3.88 (m, 5H), 3.07-2.89 (m, 4H), 1.36-1.31 (m, 6H). LC-MS(ESI): m/z=591 [M+H]⁺

Example 318(R)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-one318

To a suspension of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (200 mg, 0.42 mmol) in THF (3 mL) was addeddiisopropylethylamine (0.22 mL, 1.26 mmol), HATU (175 mg, 0.46 mmol) andD-(−)-lactic acid (41 mg, 0.46 mmol). The reaction mixture was stirredat RT for 18 hours and then concentrated in vacuo. The resultant residuewas partitioned between DCM and an aqueous saturated sodium bicarbonatesolution and the organic layer was washed with water followed by brine,dried (Na₂SO₄) and concentrated in vacuo. The resultant residue waspurified by flash chromatography (SiO₂, 0-5% MeOH in DCM) to give acream solid that was freeze-dried from methanol and water to give 318 asa white solid (59 mg, 32%). LCMS: R_(T)=4.44 min, [M+H]⁺=440. ¹H NMR δ(ppm) (DMSO-d6): 8.30 (1H, d, J=8.19 Hz), 8.05 (1H, s), 7.18 (1H, ddd,J=8.24, 4.14, 1.84 Hz), 7.01 (1H, s), 5.82-5.72 (1H, m), 5.04 (1H, s),4.65-4.55 (1H, m), 4.35-4.29 (2H, m), 4.28-4.17 (2H, m), 4.11 (1H, dd,J=13.38, 6.69 Hz), 3.86-3.75 (2H, m), 3.42-3.36 (2H, m), 1.50 (6H, d,J=6.59 Hz), 1.16 (3H, d, J=6.70 Hz)

Example 3192-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide319

To a suspension of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (200 mg, 0.42 mmol) in THF (3 mL) was added potassiumcarbonate (174 mg, 1.26 mmol) and 2-bromoacetamide (63 mg, 0.46 mmol)and the reaction mixture was stirred at RT for 18 hours. The volatileswere evaporated in vacuo and the residue partitioned between DCM and anaqueous saturated sodium bicarbonate solution. The organic layer waswashed with water followed by brine, dried (MgSO₄), concentrated invacuo and the residue purified by flash chromatography (SiO₂, 0-5% MeOHin DCM) to give 319 isolated as a cream solid after freeze drying frommethanol and water (40 mg, 22%). LCMS: R_(T)=3.03 min, [M+H]⁺=425. ¹HNMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.18 Hz), 8.05 (1H, s), 7.20 (1H,dd, J=8.24, 1.83 Hz), 7.08 (1H, s), 7.00 (2H, d, J=1.87 Hz), 5.83-5.73(1H, m), 4.34-4.28 (2H, m), 3.69-3.62 (2H, m), 3.63-3.52 (1H, m),3.41-3.35 (2H, m), 3.21-3.14 (2H, m), 2.99 (2H, s), 1.50 (6H, d, J=6.59Hz)

Example 3202-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene320

To a solution of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (200 mg, 0.42 mmol) in IMS (industrial methylated spirits,3 mL) was added triethylamine (0.20 mL, 1.47 mmol) and methyl vinylsulfone (0.09 mL, 1.05 mmol) and the reaction mixture was stirred at RT(room temperature) for 18 hours. The reaction mixture was concentratedin vacuo and the residue purified by flash chromatography (SiO₂, 0-5%MeOH in DCM). Freeze-drying from methanol and water gave 320 as a paleyellow solid (135 mg, 68%). LCMS: R_(T)=3.10 min, [M+H]⁺=474. ¹H NMR δ(ppm) (DMSO-d6): 8.35 (1H, d, J=8.19 Hz), 8.11 (1H, s), 7.29 (1H, d,J=8.27 Hz), 7.20 (1H, s), 5.85-5.76 (1H, m), 4.41-4.35 (3H, m), 4.14(3H, d, J=59.98 Hz), 3.68 (2H, s), 3.53-3.41 (3H, m), 3.13 (3H, s), 1.55(6H, d, J=6.60 Hz). 2 Protons obscured by water peak

Example 3212-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(propane-2-sulfonyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene321

Following the procedure for 395,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefree base 235, diisopropylethylamine and isopropylsulfonyl chloride werereacted. The reaction mixture was loaded directly onto a silica columnwith no aqueous work-up to give 321 isolated as a solid (57 mg, 25%).LCMS: R_(T)=12.20 min, [M+H]⁺=474. ¹H NMR δ (ppm) (CDCl₃): 8.39 (1H, d,J=8.20 Hz), 7.93 (1H, s), 7.21 (1H, dd, J=8.21, 1.89 Hz), 7.06 (1H, d,J=1.84 Hz), 5.96-5.88 (1H, m), 4.42 (2H, t, J=5.00 Hz), 4.29 (2H, t,J=8.23 Hz), 4.15 (2H, t, J=7.30 Hz), 3.84-3.78 (1H, m), 3.43 (2H, t,J=5.03 Hz), 3.16 (1H, t, J=6.84 Hz), 1.64 (6H, d, J=6.62 Hz), 1.40 (6H,d, J=6.84 Hz)

Example 3222-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanol322

Following the procedure for 376,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with MeOH as the solvent and the reaction mixture was warmedto 30° C. The crude product was triturated with diethyl ether to give322 as a yellow solid (92 mg, quant.) LCMS: R_(T)=3.03 min, [M+H]⁺=412.¹H NMR δ (ppm) (DMSO-d6): 10.65 (1H, s), 8.34-8.25 (1H, m), 8.06 (1H,s), 7.27-7.20 (1H, m), 7.15 (1H, dd, J=14.90, 1.71 Hz), 5.80-5.71 (1H,m), 4.41-4.21 (5H, m), 4.20-4.08 (1H, m), 3.67-3.56 (2H, m), 3.45-3.30(2H, m), 3.26 (1H, dd, J=10.12, 5.06 Hz), 1.51-1.46 (6H, m). 2 Protonsobscured by water peak and 1 exchangeable not observed

Example 323(S)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-one323

Following the procedure for 318,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefree base 235 and L-(+)-lactic acid were reacted to give 323 isolated asan off-white solid after freeze-drying (42 mg, 29%). LCMS: R_(T)=10.71min, [M+H]⁺=440. ¹H NMR δ (ppm) (CDCl₃): 8.40-8.33 (1H, m), 7.90 (1H,s), 7.10 (1H, t, J=6.16 Hz), 6.99 (1H, d, J=8.83 Hz), 5.91-5.83 (1H, m),4.62-4.36 (5H, m), 4.21 (3H, m), 4.18-4.08 (1H, m), 3.93-3.84 (1H, m),3.40 (2H, t, J=5.01 Hz), 1.61 (6H, d, J=6.62 Hz), 1.34 (3H, d, J=6.57Hz)

Example 324N-(2-Hydroxy-ethyl)-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-isobutyramide324

Following the procedure for 453,2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionicacid was reacted with ethanolamine to give 324. MS(ESI+) 548.1. ¹H NMR(400 MHz, DMSO) δ 8.46 (s, 1H), 8.30-8.25 (m, 2H), 8.07 (s, 1H), 7.52(dd, J=8.3, 1.5, 1H), 7.41 (d, J=1.5, 1H), 7.20 (t, J=5.4, 1H), 5.86 (q,J=8.7, 2H), 4.59 (t, J=5.4, 1H), 4.40 (t, J=4.8, 2H), 3.47 (t, J=4.9,2H), 3.36 (q, J=6.0, 2H), 3.12 (q, J=6.0, 2H), 1.75 (s, 6H)

Example 3252-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(6-morpholin-4-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene325

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholinewere reacted to give 325 (0.106 g, 58%). ¹H NMR (400 MHz, CDCl₃) δ 8.62(d, J=2.1, 1H), 8.49 (d, J=1.8, 1H), 7.93 (s, 1H), 7.76 (dd, J=8.7, 2.4,1H), 7.42 (dd, J=8.4, 2.2, 1H), 7.14 (d, J=8.3, 1H), 6.73 (d, J=8.8,1H), 5.88 (dt, J=13.3, 6.6, 1H), 4.45 (t, J=5.0, 2H), 3.95-3.76 (m, 4H),3.68-3.52 (m, 4H), 3.45 (t, J=5.0, 2H), 1.65 (d, J=6.6, 6H). MS(ESI(+)): m/z 475.2 (M+H)

Example 3268-[1-(1,1-Dioxo-tetrahydro-1S-thiophen-3-yl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene326

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with1-(1,1-Dioxo-tetrahydrothiophen-3-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazoleto give 326. MS(ESI+) 537.1. ¹H NMR (400 MHz, DMSO) δ 8.45 (s, 1H),8.32-8.26 (m, 2H), 8.10 (s, 1H), 7.46 (dd, J=8.3, 1.3, 1H), 7.35 (d,J=1.2, 1H), 5.86 (q, J=8.7, 2H), 5.25 (p, J=7.4, 1H), 4.40 (t, J=4.9,2H), 3.76 (dd, J=13.7, 8.1, 1H), 3.60-3.39 (m, 4H), 3.35-3.25 (m, 1H),2.76-2.53 (m, 2H)

Example 3272-(2-Oxo-1,2-dihydro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-8-carboxylicacid amide 327 Step 1: Methyl9-(2-fluoropyridin-3-yl)-6,7-dihydrothieno[2,3-d]pyrido[3,2-b]oxepine-3-carboxylate

Methyl9-bromo-6,7-dihydrothieno[2,3-d]pyrido[3,2-b]oxepine-3-carboxylate wascoupled with 2-fluoropyridin-3-ylboronic acid under Suzuki conditions togive methyl9-(2-fluoropyridin-3-yl)-6,7-dihydrothieno[2,3-d]pyrido[3,2-b]oxepine-3-carboxylate.Yield 61%. MS(ESI+): 357.1

Step 2:2-(2-Oxo-1,2-dihydropyridin-3-yl)-4,5-dihydrobenzooxepino[4,5-d]thiophene-8-carboxylicacid

A mixture of 120 mg (0.337 mmol) of methyl9-(2-fluoropyridin-3-yl)-6,7-dihydrothieno[2,3-d]pyrido[3,2-b]oxepine-3-carboxylatein 5 ml of acetic acid and 2 ml of 4 N aqueous hydrogen chloride washeated in a sealed vial at 110° C. for 3 hours. The mixture wasconcentrated in vacuum and the residue triturated with 5 ml of water.The precipitate was collected and dried in high vacuum for 24 hours.Yield 102 mg (54%). MS(ESI+): 341.1

Step 3

2-(2-Oxo-1,2-dihydropyridin-3-yl)-4,5-dihydrobenzooxepino[4,5-d]thiophene-8-carboxylicacid was coupled with ammonium chloride, and HATU to give 327. Yield40%. MS(ESI+): 340.1. 1H NMR (400 MHz, DMSO) 12.07 (s, 1H), 8.68 (d,J=1.7, 1H), 8.16-8.03 (m, 2H), 7.78 (d, J=1.7, 1H), 7.68 (s, 1H), 7.52(s, 1H), 7.43 (t, J=8.8, 1H), 6.36 (t, J=6.7, 1H), 4.36 (s, 2H)

Example 3292,2,2-Trifluoro-1-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-ethanol329

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carbonitrile136 (0.353 g, 1.05 mmol) was dissolved in DCM (2.5 mL) and cooled at 0°C. A solution of diisobutylaluminum hydride (1M, 1.57 mL, 1.57 mmol) wasadded dropwise and the mixture was gradually allowed to warm to roomtemperature with stirring over 2 h. The reaction mixture was then pouredinto a mixture containing Rochelle's salt aqueous solution and Et₂O. Theentire mixture was stirred vigorously for an overnight period to aidpartitioning of the phases. The phases were separated and the aqueouswas extracted 3× with EtOAc. The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated to provide 354mg (99%) of the crude aldehyde,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carbaldehyde.

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carbaldehyde(0.354 g, 1.04 mmol) was dissolved in THF (7 mL) and treated with(trifluoromethyl)trimethylsilane (0.154 mL, 1.04 mmol) followed by TBAF(1M, 0.02 mL, 0.02 mmol). Stirred the resulting reaction mixture atambient temperature for 2 h. Concentrated in vacuo and re-dissolved inDMF and purified by reverse phase HPLC to give 25.6 mg (6% yield) of329. LC/MS (ESI+): m/z 411 (M+H). ¹H NMR (400 MHz, DMSO) δ 8.55 (s, 1H),8.10 (s, 1H), 7.41 (d, J=8.4, 1H), 7.10 (d, J=8.3, 1H), 6.80 (s, 1H),5.80 (dt, J=13.1, 6.5, 1H), 5.21 (d, J=6.7, 1H), 4.39 (t, J=4.9, 2H),3.45 (t, J=4.9, 2H), 1.55 (d, J=6.5, 6H)

Example 3303-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H-pyridin-2-one330

To a solution of 306 (0.275 g, 0.675 mmol) in DME (5 mL) was added 10%aq HCl (5 mL). The reaction mixture was allowed to stir and heat at 80°C. for 18 hours before cooling, concentrating under reduced pressure,and diluting with EtOAc. The solution was washed sequentially withwater, and brine, before drying over MgSO₄ and concentrating underreduced pressure to 50 mL of EtOAc and the solids were collected byfiltration to give 330 (244 mg, 89%). ¹H NMR (400 MHz, DMSO) δ 11.79 (s,1H), 9.00 (t, J=15.9, 1H), 8.10 (s, 1H), 7.67 (ddd, J=16.8, 8.8, 5.2,2H), 7.37 (d, J=5.1, 1H), 7.08 (d, J=8.4, 1H), 6.31 (t, J=6.7, 1H), 5.88(dt, J=13.2, 6.6, 1H), 4.58-4.20 (m, 2H), 3.46 (t, J=5.0, 2H), 1.55 (d,J=6.6, 6H). MS (ESI(+)): m/z 406.1 (M+H)

Example 3319-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 331

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (225 mg, 0.547 mmol) and2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazol-1-yl)propan-2-ol(174.7 mg, 0.656 mmol) were reacted to give 331 (20.0 mg, 8% yield, M+1471.2).

Example 3322-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propan-1-ol332

2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionicacid (0.250 g, 0.000496 mol) in dry tetrahydrofuran (1.0 mL, 0.012 mol)cooled to 0° C. Lithium tetrahydroaluminate (1M solution in THF, 1.0 mL,0.0010 mol), was added dropwise at 0° C. and the mixture was allowed towarm to room temperature and stirred for 2 h. The reaction was quenchedwith saturated Na₂SO₄ until no more hydrogen evolution was observed.MgSO₄ was added and the solution was filtered and rinsed with copiousamounts of methylene chloride. The solvent was removed in vacuo and thecrude material was purified by reverse-phase HPLC to give 332 (35.4 mg)as a colorless solid. MS(ESI+) 491.1.

Example 333N2-(2-chloro-5-(piperazine-1-carbonyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide333

To a mixture of tert-butyl piperazine-1-carboxylate (1.7 g, 9.13 mmol),DIPEA (3 mL), HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (3.0 g, 6.09 mmol) under nitrogen atmosphere at room temperature.The reaction mixture was stirred overnight, diluted with water,extracted with EtOAc. The organic layer was dried over Na₂SO₄,concentrated in vacuo to give tert-butyl4-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoyl)piperazine-1-carboxylate(3.9 g, yield: 97%). LC-MS: (ESI, m/z)=682 [M+Na]⁺

A suspension of tert-butyl4-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoyl)piperazine-1-carboxylate(500 mg, 0.76 mmol), Pd(OAc)₂ (9 mg, 0.038 mmol), Xantphos (44 mg, 0.076mmol), MeNH₂.HCl (77 mg, 1.14 mmol) and Na₂CO₃ (242 mg, 2.28 mmol) intoluene (10 mL) was heated at 80° C. under atmosphere of CO from balloonfor overnight. Then it was filtrated and concentrated, the crude productwas purified by pre-TLC (DCM/MeOH=10:1 as eluted solvent) to givetert-butyl4-(4-chloro-3-(N-methyl-8-(methylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoyl)piperazine-1-carboxylate(390 mg, yield: 80%). ¹H NMR (DMSO, 400 MHz): δ7.59-7.26 (m, 8H, ArH,NH), 4.26 (t, J=5.2 Hz, 2H, CH₂), 3.57-2.80 (m, 18H, CH₂, CH₃), 1.47 (s,9H, CH₃)

A solution of HCl in EtOAc (4M, 20 mL) was slowly added into a solutionof tert-butyl4-(4-chloro-3-(N-methyl-8-(methylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoyl)piperazine-1-carboxylate(390 mg, 0.61 mmol) in EtOAc (5 mL) at 0° C. The mixture was stirred atroom temperature for overnight. The solids were filtered and washed withEtOAc, dried to give 333 (250 mg, yield 71%). ¹H NMR (MeOD, 400 MHz):δ7.76-7.42 (m, 7H, ArH, NH), 6.90 (s, 1H, ═CH), 4.23-2.89 (m, 19H).LC-MS: (ESI, m/z)=539 [M+H]⁺, 561 [M+Na]⁺

Example 334N2-(2-chloro-5-(piperazine-1-carbonyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide334

A suspension of tert-butyl4-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoyl)piperazine-1-carboxylate(500 mg, 0.76 mmol), Pd(OAc)₂ (9 mg, 0.038 mmol), Xantphos (44 mg, 0.076mmol), MeSO₂(CH₂)₂NH₂.HCl (182 mg, 1.14 mmol) and Na₂CO₃ (242 mg, 2.28mmol) in toluene (10 mL) was heated at 80° C. under atmosphere of COfrom balloon for overnight. Then it was filtrated and concentrated, thecrude product was purified by pre-TLC (DCM:MeOH=10:1 as eluted solvent)to give tert-butyl4-(4-chloro-3-(N-methyl-8-(2-(methylsulfonyl)ethylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoyl)piperazine-1-carboxylate(350 mg, yield 63%). ¹H NMR (CDCl₃, 400 MHz): δ 7.60-7.34 (m, 8H, ArH,NH), 4.26-2.80 (m, 22H, CH₂, CH₃), 1.48 (s, 9H, 3CH₃).

A solution of HCl in EtOAc (4M, 20 mL) was slowly added into a solutionof tert-butyl4-(4-chloro-3-(N-methyl-8-(2-(methylsulfonyl)ethylcarbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoyl)piperazine-1-carboxylate(350 mg, 0.48 mmol) in EtOAc (5 mL) at 0° C. The mixture was stirred atroom temperature for overnight. The solids were filtered and washed withEtOAc, dried to give 334 (176.6 mg, yield: 55%). ¹H NMR (MeOD, 400 MHz):δ7.77-7.44 (m, 7H, ArH, NH), 6.93 (s, 1H, ═CH), 4.24-3.04 (m, 23H).LC-MS: (ESI, m/z)=631 [M+H]¹

Example 3355-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-ylamine335

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (268mg, 1.2 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10 mmol)and CH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube, and themixture was heated by microwave at 120° C. for 20 min under N₂. Thereaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to give 335 (179.7 mg, yield: 38%). ¹HNMR (DMSO-d₆, 400MHz): δ8.54 (s, 1H), 8.27 (s, 1H), 7.92-7.87 (m, 2H), 7.42 (t, J=0.8 Hz,1H), 7.73-7.72 (m, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.43 (t, J=8.8 Hz, 1H),7.17 (s, 1H), 6.54 (d, J=8.8 Hz, 1H), 6.28 (s, 1H), 4.26 (s, 2H), 3.11(s, 2H). ESI-MS: m/z=475 [M+H⁺]

Example 3362-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene336

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (262mg, 1.2 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10 mmol)and CH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube, and themixture was heated by microwave at 120° C. for 20 min under N₂. Thereaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to give 336 (168.7 mg, yield: 36%). ¹HNMR (DMSO-d₆, 400MHz): δ9.04 (s, 1H), 8.28 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.91-7.87 (m,2H), 7.76-7.71 (m, 1H), 7.48-7.45 (m, 2H), 7.36-7.34 (m, 1H), 7.14 (s,1H), 4.30 (s, 2H), 3.14 (s, 2H), 2.52 (s, 3H). ESI-MS: m/z=474 [M+H⁺]

Example 3372-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-methoxy-4-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene337

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),2-Methoxy-4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(298 mg, 1.2 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10mmol) and CH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube,and the mixture was heated by microwave at 120° C. for 20 min under N₂.The reaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to afford 337 (120.8 mg, yield: 24%). ¹HNMR (DMSO-d₆,400 MHz): δ8.29 (s, 1H), 8.20 (s, 1H), 7.92-7.81 (m, 1H), 7.70 (t, J=2.4Hz, 1H), 7.51-7.41 (m, 3H), 7.24 (s, 2H), 6.75 (s, 1H), 4.31 (s, 2H),3.89 (s, 3H), 3.19 (s, 2H), 2.32 (s, 3H). ESI-MS: m/z=504 [M+H⁺]

Example 3382-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene338

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol),4-[4-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-morpholine(370 mg, 1.2 mmol), Cs₂CO₃ (650 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.10mmol) and CH₃CN—H₂O (1:1, 4 mL) were added in a 10 mL of sealed tube,and the mixture was heated by microwave at 120° C. for 20 min under N₂.The reaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative HPLC to give 338 (211 mg, yield: 38%). ¹HNMR (DMSO-d₆, 400MHz): δ8.69 (s, 1H), 8.28 (s, 1H), 7.96-7.90 (m, 1H), 7.85-7.70 (m, 2H),7.52-7.41 (m, 2H), 7.17 (s, 2H), 3.75-3.72 (m, 4H), 3.13 (s, 6H), 2.32(s, 3H). ESI-MS: m/z=559 [M+H⁺]

Example 339(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-dimethyl-amine339

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(470 mg, 1.0 mmol), from the procedure for 249, Dimethyl-amine (98 mg,1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mLof sealed tube, and the mixture was heated by microwave at 150° C. for120 min under N₂. The reaction mixture was filtered to gather thesolution and water was added. The mixture was extracted by DCM (20mL×3). The combined organic layers were dried over Na₂SO₄, concentratedin vacuo, and purified by preparative HPLC to give 339 (61.4 mg, yield:12%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.06 (d,J=9.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.73-7.71 (m, 2H), 7.42-7.40 (m, 2H),7.19 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H),4.31 (s, 2H), 3.16-3.11 (m, 8H). ESI-MS: m/z=503 [M+H⁺]

Example 3402-(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-ylamino)-ethanol340

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(470 mg, 1.0 mmol), from the procedure for 249,2-Methanesulfonyl-ethylamine (147 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol)and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture washeated by microwave at 150° C. for 120 min under N₂. The reactionmixture was filtered to gather the solution and water was added. Themixture was extracted by DCM (20 mL×3). The combined organic layers weredried over Na₂SO₄, concentrated in vacuo, and purified by preparativeHPLC to give 340 (68.9 mg, yield: 14%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.63(s, 1H), 8.30 (s, 1H), 7.90-7.85 (m, 2H), 7.70-7.70 (m, 2H), 7.41-7.38(m, 2H), 7.19 (s, 2H), 6.90-6.88 (m, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.75(s, 1H), 4.29 (s, 2H), 3.56-3.55 (m, 2H), 3.40-3.38 (m, 2H), 3.15 (s,2H). ESI-MS: m/z=519 [M+H⁺]

Example 341(5-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-pyridin-2-yl)-(2-methoxy-ethyl)-amine341

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(470 mg, 1.0 mmol), from the procedure for 249, 2-Methoxy-ethylamine (90mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10mL of sealed tube, and the mixture was heated by microwave at 150° C.for 120 min under N₂. The reaction mixture was filtered to gather thesolution and water was added. The mixture was extracted by DCM (20mL×3). The combined organic layers were dried over Na₂SO₄, concentratedin vacuo, and purified by preparative HPLC to give 341 (105.5 mg, yield:20%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.63 (s, 1H), 8.31 (s, 1H), 7.94-7.88(m, 2H), 7.76-7.68 (m, 2H), 7.46-7.38 (m, 2H), 7.21 (s, 2H), 6.99 (s,1H), 6.63 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.49 (s, 4H), 3.29 (s, 3H),3.15 (s, 2H). ESI-MS: m/z=533 [M+H⁺]

Example 3422-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-pyridin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene342

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and pyridin-3-ylboronic acid were reacted to give 342(0.120 g, 22%). ¹H NMR (400 MHz, DMSO) δ 8.91 (d, J=1.7, 1H), 8.72 (d,J=2.3, 1H), 8.57 (dd, J=7.2, 3.7, 1H), 8.11 (s, 1H), 8.07 (d, J=8.0,1H), 7.69 (dd, J=8.4, 2.3, 1H), 7.53 (dd, J=7.9, 4.8, 1H), 7.22 (d,J=8.4, 1H), 5.79 (dt, J=13.2, 6.6, 1H), 4.44 (t, J=4.9, 2H), 3.49 (t,J=4.9, 2H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 390.1 (M+H)

Example 3432-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(5-methoxy-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene343

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine werereacted to give 343 (0.062 g, 60%). ¹H NMR (500 MHz, DMSO) δ 8.72 (d,J=2.4, 1H), 8.50 (d, J=1.8, 1H), 8.29 (d, J=2.7, 1H), 8.11 (s, 1H), 7.71(dd, J=8.4, 2.4, 1H), 7.64 (dd, J=2.6, 2.0, 1H), 7.21 (d, J=8.4, 1H),5.82 (dd, J=13.2, 6.6, 1H), 4.43 (t, J=5.0, 2H), 3.92 (s, 3H), 3.49 (t,J=5.0, 2H), 1.56 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)

Example 3442-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethylamine344

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with2-{2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-isoindole-1,3-dioneto giveN-[2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-phthalamicacid. MS(ESI+) 610.1

To a solution ofN-[2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-phthalamicacid (0.2000 g, 0.0003281 mol) in ethanol (3 mL, 0.05 mol) was addedhydrazine (0.01133 mL, 0.0003609 mol). The mixture was heated to 60° C.overnight, cooled to room temperature and concentrated in vacuo. Thecrude was purified by reverse-phase HPLC to give 344 (13.6 mg) as acolorless solid. MS(ESI+) 462.1. ¹H NMR (400 MHz, DMSO) δ 8.31-8.25 (m,3H), 7.99 (s, 1H), 7.45 (dd, J=8.3, 1.8, 1H), 7.33 (d, J=1.8, 1H), 5.87(q, J=8.7, 2H), 4.40 (t, J=5.0, 2H), 4.11 (t, J=6.3, 2H), 3.47 (t,J=5.0, 2H), 2.98 (t, J=6.3, 2H)

Example 3452-Hydroxy-1-(3-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidin-1-yl)-propan-1-one345

Similarly to as described in General Procedure C,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 was reacted with tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateto give3-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylicacid tert-butyl ester which was used without purification.

3-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylicacid tert-butyl ester (2.2 mmol) was dissolved in 5 mL of methylenechloride and treated with 2 mL of trifluoroacetic acid. After 2 h,aqueous workup and concentration of the organics gave the crudedeprotected azetidine as a colorless solid that was used in the nextstep without purification. Crude8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(190 mg) was dissolved in 3 mL of THF and treated sequentially withDIPEA (0.23 mL, 1.3 mmol), lactic acid (0.10 L, 1.3 mmol) and HATU (333mg, 0.88 mmol). After 2 h at room temperature, aqueous workup andextraction with ethylacetate gave a crude solid that was purified byreverse phase HPLC to give 345 as a colorless solid (35 mg, 16%). LCMS:506.2. ¹H NMR (400 MHz, DMSO) δ 8.47 (d, J=2.3 Hz, 1H), 8.33 (d, J=8.3Hz, 1H), 8.11 (s, 2H), 7.48 (dd, J=8.3, 1.7 Hz, 1H), 7.36 (d, J=1.7 Hz,1H), 5.84 (m, 1H), 5.28 (m, 1H), 5.23-5.17 (m, 1H), 4.80-4.69 (m, 1H),4.60-4.50 (m, 1H), 4.39 (t, J=5.0 Hz, 2H), 4.34 (m, 1H), 4.22-4.12 (m,2H), 3.45 (t, J=5.0 Hz, 2H), 1.56 (d, J=6.6 Hz, 6H), 1.23 (d, J=6.7 Hz,3H).

Example 3462-{4-[2-(4-Isopropyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol346

Similarly to as described in General Procedure C,8-bromo-2-(4-isopropyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranylether was accomplished by adding 2N HCl to the crude reaction mixture.Purification by reverse phase HPLC gave 346 as a colorless solid (112mg). LCMS: 491.1. ¹H NMR (400 MHz, DMSO) δ 8.27 (d, J=13.7 Hz, 1H), 8.23(s, 1H), 7.95 (s, 1H), 7.44 (dd, J=8.3, 1.7 Hz, 1H), 7.32 (d, J=1.7 Hz,1H), 5.45-5.29 (m, 1H), 4.91 (t, J=5.3 Hz, 1H), 4.41 (t, J=5.0 Hz, 2H),4.16 (t, J=5.6 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H), 3.48 (t, J=5.0 Hz, 2H),1.70 (t, J=11.9 Hz, 6H)

Example 3472-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-propan-1-ol347

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), 1-(trimethylsilyloxy)propan-2-amine (211 mg, 1.44mmol), ^(t)BuONa (47 mg, 0.48 mmol), Pd(OAc)₂ (16 mg, 0.1 mmol), andXphos (68 mg, 0.144 mmol) in dioxane (2 mL) was bubbled N₂ for 10 minand then stirred at 125° C. for 7 min under the irradition of microwave.The mixture was filtered over ceilite. The filtrate was concentrated todryness and purified by pre-TLC (EtOAc) and pre-HPLC to afford 40 mg of347. (yield: 13%). ¹H NMR (CDCl₃, 400 MHz): δ8.02 (s, 1H), 7.49 (q,J=5.6, 8.8 Hz, 1H), 7.12-6.99 (m, 4H), 6.21 (d, J=4.8 Hz, 1H), 4.20-3.04(m, 8H), 2.28 (s, 1H), 1.19-1.15 (m, 3H). LC-MS (ESI): m/z=456 [M+H]⁺

Example 3481-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazin-1-yl)-ethanone348

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(208 mg×4, 2.0 mmol), tert-butyl piperazine-1-carboxylate (445 mg, 2.4mmol), Pd(OAc) (45 mg, 0.20 mmol), Xphos (95 mg, 2.0 mmol), t-BuONa (460mg, 4.0 mmol) and dioxane (4 mL) were added in a 10 mL of sealed tube,and the mixture was heated by microwave at 112° C. for 7 min under N₂.The reaction mixture was filtered to gather the solution and water wasadded. The mixture was extracted by DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo, and purified bypreparative TLC (DCM/EtOAc=10:1) to give4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazine-1-carboxylicacid tert-butyl ester (612 mg, yield: 54%). ¹HNMR (DMSO-d₆, 400 MHz):δ8.30 (s, 1H), 7.99-7.90 (m, 1H), 7.79-7.70 (m, 2H), 7.32 (s, 1H), 7.27(s, 1H), 7.25 (s, 1H), 6.78 (d, J=8.8 Hz, 1H), 4.19 (s, 4H), 4.04-4.02(m, 4H), 3.44 (m, 1H), 3.12 (s, 1H), 1.57 (s, 9H) ESI-MS: m/z=567 [M+H⁺]

4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazine-1-carboxylicacid tert-butyl ester (0.61 g, 1.08 mmol) was dissolved in EtOAc, andEtOAc—HCl was added dropwise into the solution. And them the mixture wasstirred at room temperature for 2 h. The reaction mixture was filteredto gather the solid. The resulting solid was washed by DCM (10 mL) togive2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperazin-1-yl-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azuleneas HCl salt (420 mg, yield: 77%). ¹HNMR (D₂O, 400 MHz): δ8.05 (s, 1H),7.45-7.39 (m, 1H), 7.23 (t, J=8.8 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 7.01(s, 1H), 6.99 (d, J=1.6 Hz, 1H), 6.99 (d, J=4.8 Hz, 1H), 3.97 (s, 1H),3.39 (s, 4H), 3.19 (s, 4H), 2.83 (s, 2H) ESI-MS: m/z=503 [M+H⁺]

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperazin-1-yl-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(150 mg, 0.3 mmol) was dissolved in THF (20 mL), and DIPEA (155 mg, 1.2mmol) was added. Acetyl chloride (28 mg, 0.36 mmol) was added dropwiseinto the solution. And then the reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was concentrated in vacuo,and then dissolved in DCM. The mixture was washed by water, dried byNa₂SO₄, concentrated in vacuo, and purified by prep. TLC(DCM/EtOAc=10:1) to give 348 (42.6 mg, yield: 28%). ¹HNMR (DMSO, 400MHz): δ8.29 (s, 1H), 7.97-7.88 (m, 1H), 7.78 (t, J=2.4 Hz, 1H), 7.47 (t,J=8.4 Hz, 1H), 7.27-7.24 (m, 2H), 6.80 (d, J=8.8 Hz, 1H), 4.20 (s, 1H),3.63 (s, 4H), 3.33 (s, 4H), 3.11 (s, 2H), 2.07 (s, 3H). ESI-MS: m/z=509[M+H⁺]

Example 3491-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-[1,4]diazepan-1-yl)-ethanone349

Compound 350 (70 mg, 0.14 mmol) was dissolved in THF, DIPEA (56 mg, 0.56mmol) was added, and acetyl chloride (14 mg, 0.17 mmol) was added intothe solution. And the reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated in vacuo, then dissolvedin DCM. The organic layer was washed by water, dried by Na2SO4,concentrated in vacuo, and purified by TLC (DCM/EtOAc=4:1) to get 349(51.9 mg, yield: 67%)¹HNMR (DMSO-d₆, 400 MHz): δ8.30 (s, 1H), 8.16 (s,1H), 7.96-7.70 (m, 1H), 7.35-7.29 (m, 1H), 7.28-7.25 (m, 1H), 7.21 (s,1H), 7.20-7.16 (m, 1H), 6.97 (t, J=11.4 Hz, 1H), 4.17 (d, J=5.2 Hz, 2H),3.68 (s, 2H), 3.30 (s, 6H), 3.10 (s, 2H), 1.70 (s, 3H), 1.28 (t, J=6.0Hz, 1H). ESI-MS: m/z=523 [M+H⁺]

Example 3509-[1,4]Diazepan-1-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene350

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol), 1,4-diazepane (120 mg, 1.2 mmol), Pd₂(dba)₃ (210 mg,0.3 mmol), Xphos (142 mg, 0.3 mmol), t-BuONa (576 mg, 6 mmol) anddioxane (6 mL) were added into a 10 mL of sealed tube, and the mixturewas heated by microwave at 112° C. for 7 min under N₂. The reactionmixture was filtered to gather the solution. The water was added andextracted by DCM (50 mL×3). The combined organic layers were dried overNa₂SO₄, concentrated in vacuo, and separated by column (DCM/EtOAc=4:1)to get 350 (120 mg, yield: 25%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.04 (s,1H), 7.97 (s, 1H), 7.67-7.65 (m, 1H), 7.50-7.46 (m, 1H), 7.20 (t, J=8Hz, 1H), 7.02 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.36 (d, J=8.8 Hz, 1H),3.92 (d, J=4.4 Hz, 2H), 3.37-3.31 (m, 4H), 2.87 (d, J=4.4 Hz, 4H), 2.72(s, 2H), 2.57 (s, 2H), 1.59 (s, 2H). ESI-MS: m/z=481 [M+H⁺]

Example 3512-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[(3R,5S)-3,5-dimethyl-4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene351

To a solution of compound 316 (100 mg, 0.17 mmol) in tetrahydrofuran (5mL) was added a solution of borane/dimethylsulfane (10 mol/L, 2 mL)dropwise at 0° C. After the addition was completed, the reaction mixturewas stirred at that temperature for 30 min and then allowed to warm to50° C. After stirred for another 1 hour the reaction mixture wasquenched by adding 15 mL of methanol and 5 mL of 1 M HCl aqueoussolution slowly. The mixture was stirred at room temperature for 2 hoursbefore concentration to the residue. The mixture was treated withdichloromethane and water. The organic layer was concentrated to drynessand the crude was purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 60mg of 351. (Yield: 61%)¹H NMR (CDCl₃, 400 MHz): δ8.02 (s, 1H), 7.51-7.46(m, 1H), 7.09-6.97 (m, 4H), 6.45 (d, J=8.8 Hz, 1H), 4.18 (t, J=4.8 Hz,2H), 3.84-3.80 (m, 2H), 3.27 (q, J=9.6 Hz, 2H), 3.07 (t, J=4.8 Hz, 2H),2.84 (d, J=6.8 Hz, 2H), 2.57-2.51 (m, 2H), 1.22-1.34 (d, J=6.0 Hz, 6H).LC-MS (ESI): m/z=577 [M+H]⁺

Example 3524-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazin-2-one352

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(100 mg, 0.24 mmol), piperazin-2-one (48 mg, 0.48 mmol), ^(t)BuONa (47mg, 0.48 mmol), Pd₂(dba)₃ (22 mg, 0.2 mmol) and Xphos (23 mg, 0.048mmol) in dioxane (2 mL) was bubbled N₂ for 10 min and then stirred at115° C. for 5 min under the irradition of microwave. The mixture wasfiltered by celite. The filtrate was concentrated to dryness andpurified by pre-TLC (EtOAc) and pre-HPLC to afford 15 mg of 352. (yield:13%)¹H NMR (CDCl₃, 400 MHz): δ8.02 (s, 1H, ArH), 7.49-6.96 (m, 5H), 6.41(d, J=8.8 Hz, 1H), 5.95 (s, 1H), 4.19 (t, J=4.8 Hz, 2H), 3.99 (s, 2H),3.76 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.2 Hz, 2H), 3.06 (t, J=4.8 Hz, 2H).LC-MS (ESI): m/z=481 [M+H]⁺

Example 3531-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-piperidin-1-yl)-ethanone353

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(208 mg, 0.5 mmol), 1-(4-aminopiperidin-1-yl)ethanone (170 mg, 0.6mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), Xphos (14 mg, 0.05 mmol), t-BuONa(115 mg, 1.0 mmol) and dioxane (2.0 ml) was added into a 10 mL of sealedtube, and the mixture was heated by microwave at 112° C. for 7 min underN₂. The reaction mixture was filtered to gather the solution and waterwas added. The mixture was extracted by DCM (20 mL×3). The combinedorganic layers were dried over Na₂SO₄, concentrated in vacuo, andpurified by preparative TLC (DCM/EtOAc=10:1) to get 353 (115 mg, yield:44%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.24 (s, 1H), 7.87-7.83 (m, 1H), 7.70(t, J=2.8 Hz, 1H), 7.69 (t, J=2.8 Hz, 1H), 7.38 (s, 1H), 7.07 (d, J=8.8Hz, 1H), 6.43 (d, J=11.2 Hz, 1H), 6.37 (d, J=8.8 Hz, 1H), 4.14-4.03 (m,4H), 3.69-3.66 (m, 2H), 3.06-3.04 (m, 2H), 2.64 (t, J=2.0 Hz, 1H), 2.87(s, 3H), 1.88-1.78 (m, 2H), 1.23-1.22 (m, 2H). ESI-MS: m/z=523 [M+H⁺]

Example 3542-Methyl-1-{4-[2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-propan-2-ol354

Following the procedure for 114,8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 354. MS(ESI+) 500.1. ¹H NMR (400 MHz, DMSO) δ 8.56 (dd, J=4.5,1.6, 2H), 8.24 (s, 1H), 8.15 (s, 1H), 8.03 (d, J=8.3, 1H), 7.93 (s, 1H),7.32 (dd, J=8.3, 1.8, 1H), 7.26 (d, J=1.8, 1H), 7.23-7.19 (m, 2H), 6.12(s, 2H), 4.71 (s, 1H), 4.35 (t, J=5.0, 2H), 4.03 (s, 2H), 3.43 (t,J=5.0, 2H), 1.09 (s, 6H)

Example 3552-Methyl-1-(4-{2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propan-2-ol355

To a solution of8-Bromo-2-(1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.430 g, 1.23 mmol) in N,N-Dimethylformamide (17.2 mL, 222 mmol) wasadded Cesium Carbonate (0.805 g, 2.47 mmol). After 45 min.2-iodo-1,1,1-trifluoro-ethane (0.241 mL, 2.47 mmol) was added to thereaction mixture. The reaction mixture was stirred at 50 C 4 h. Thereaction was quenched with water then extracted with EtOAc 2×. Theorganic layers was combined, dried Na2SO4, concentrated and purified bychromatography (EtOAc/Hex) (eluted at 35%) to give8-Bromo-2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.MS: (ESI+)=330.1.

8-Bromo-2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(110.0 mg, 0.2557 mmol) dissolved in Acetonitrile (0.534 mL, 10.2 mmol)and with dissolved 2.00 M of Potassium carbonate in Water (0.256 mL).Degas by bubbling nitrogen for 5 min. The reaction was charged with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol(102 mg, 0.384 mmol) then Tetrakis(triphenylphosphine)palladium(0)(41.36 mg, 0.03579 mmol). The reaction was heated in microwave at 140 Cfor 10 min. The reaction was cooled to r.t. then extracted with ethylacetate. Combined organics concentrated and purified by reverse phaseHPLC to give 355. MS: (ESI+)=490.1. ¹H NMR (400 MHz, DMSO) δ 8.24 (d,J=8.3 Hz, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.41 (dd,J=8.3, 1.8 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 5.74(q, J=8.9 Hz, 2H), 4.71 (s, 1H), 4.37 (t, J=5.0 Hz, 2H), 4.03 (s, 2H),3.40 (t, J=5.0 Hz, 2H), 1.09 (s, 6H)

Example 3563-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-4,4-dimethyl-oxazolidin-2-one356 Step 1: 1-(1-Hydroxy-2-methylpropan-2-yl)thiourea

Following the procedure in US2008/45579, 2008,2-amino-2-methylpropan-1-ol was coupled with benzoylisothiocyanate togive N-(1-hydroxy-2-methylpropan-2-ylcarbamothioyl)benzamide which wasthen reacted with lithium hydroxide to give1-(1-hydroxy-2-methylpropan-2-yl)thiourea. 1H NMR (400 MHz, DMSO) δ 7.09(s, 2H), 5.01 (s, 1H), 3.44 (s, 2H), 1.30 (s, 6H)

Step 2:2-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-ol

A mixture of 0.67 g (5.0 mmol) of1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol washeated under reflux for 3 hours. The mixture was concentrated, theresidue purified on silica gel column eluting the product with 10% ofmethanol in dichloromethane. Yield 1.38 g (75%). MS(ESI+): 369.3

Step 3:3-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-yl)-4,4-dimethyloxazolidin-2-one

Triphosgene (148 mg, 0.500 mmol) was added to a mixture of 185 mg (0.500mmol) of2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-oland 0.522 ml (3.00 mmol) of diisopropylethylamine in 7.0 ml of methylenechloride. The reaction mixture was stirred for 3 hours and concentratedin vacuum. The residue was partitioned between ethyl acetate and 5%aqueous citric acid. The organic extracts were washed with water, brine,dried over magnesium sulfate and concentrated in vacuum. Yield 194 mg(98%). MS(ESI+): 396.3

Step 4

3-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-yl)-4,4-dimethyloxazolidin-2-onewas coupled with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olto give 356. Yield 22%. MS(ESI+): 455.1. 1H NMR (400 MHz, DMSO) δ 8.16(d, J=8.3, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.37 (dd, J=8.3, 1.8, 1H),7.24 (d, J=1.8, 1H), 4.71 (s, 1H), 4.32 (d, J=6.9, 4H), 4.05-4.00 (m,2H), 3.25 (t, J=5.0, 2H), 1.76 (s, 6H), 1.09 (s, 6H)

Example 3572-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-piperidin-1-yl}-acetamide357

Following the procedure for 319,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt was alkylated with bromoacetamide to give 357 isolated as awhite solid (167 mg, 86%). LCMS: R_(T)=7.55 min, [M+H]⁺=453. ¹H NMR δ(ppm) (DMSO-d6): 8.23 (1H, d, J=2.30 Hz), 8.06 (1H, s), 7.14 (1H, dd,J=8.34, 2.37 Hz), 7.10 (2H, s), 6.95 (1H, d, J=8.26 Hz), 5.79-5.68 (1H,m), 4.33-4.27 (2H, m), 3.41-3.35 (2H, m), 2.92-2.81 (4H, m), 2.50 (1H,m), 2.17 (2H, dd, J=12.36, 10.20 Hz), 1.78 (2H, d, J=12.48 Hz),1.73-1.61 (2H, m), 1.53 (6H, d, J=6.61 Hz)

Example 358(R)-2-Hydroxy-1-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-piperidin-1-yl}-propan-1-one358

Following the procedure for 318,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt was reacted to give 358 isolated as a white solid (90 mg, 45%).LCMS: R_(T)=11.57 min, [M+H]⁺=468. ¹H NMR δ (ppm) (DMSO-d6): 8.19 (1H,d, J=2.28 Hz), 8.06 (1H, s), 7.14 (1H, d, J=8.35 Hz), 6.96 (1H, d,J=8.24 Hz), 5.78-5.70 (1H, m), 4.83 (1H, s), 4.48 (1H, d, J=12.45 Hz),4.42 (1H, q, J=6.52 Hz), 4.30 (2H, t, J=5.02 Hz), 4.08 (1H, s), 3.38(2H, t, J=5.02 Hz), 3.09 (1H, t, J=13.26 Hz), 2.84-2.75 (1H, m),2.71-2.59 (1H, m), 1.84 (2H, d, J=12.55 Hz), 1.57-1.47 (8H, m), 1.17(3H, t, J=5.38 Hz)

Example 359(S)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin-1-yl}-propan-1-one359

Following the procedure for 318,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand sodium L-lactate were reacted in DMF to give 359. LCMS: R_(T)=10.69min, [M+H]⁺=440. ¹H NMR δ (ppm) (CDCl₃): 8.36 (1H, s), 7.90 (1H, s),7.20-7.11 (1H, m), 7.09-7.01 (1H, m), 5.84-5.75 (1H, m), 4.62-4.30 (4H,m), 4.26-4.07 (3H, m), 3.98-3.87 (1H, m), 3.43-3.35 (2H, m), 1.61 (6H,d, J=6.65 Hz), 1.32 (3H, dd, J=10.70, 6.64 Hz). 1 Exchangeable notobserved

Example 360N2-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide360

To a mixture of3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (2.5 g, 5.07 mmol) in THF (50 mL) was added EDCI (1.94 g, 10.14mmol), HOBt (1.03 g, 7.61 mmol), DIPEA (5 mL) and 3-hydroxyazetidinehydrochloride (0.83 g, 7.61 mmol) by sequence under nitrogen atmosphereat room temperature. The reaction mixture was stirred overnight, dilutedwith water, extracted with EtOAc. The organic layer was dried overNa₂SO₄, concentrated in vacuo. The crude product was purified by flashcolumn chromatography on silica gel (eluted by hexanes:EtOAc=1:2) togive8-bromo-N-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(1.6 g, yield 58%). LC-MS: (ESI, m/z)=547 [M+H]⁺

A suspension of8-bromo-N-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(500 mg, 0.91 mmol), Pd(OAc)₂ (10 mg, 0.046 mmol), Xantphos (53 mg,0.091 mmol), MeNH₂.HCl (92 mg, 1.37 mmol) and Na₂CO₃ (289 mg, 2.73 mmol)in toluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphereof CO from balloon for overnight. Then it was filtrated andconcentrated, the crude product was purified by flash columnchromatography on silica gel (DCM:MeOH=20:1 as eluted solvent) to give awhite solid which was washed with MeOH and dried to give 360 (221.5 mg,yield 46%). ¹H NMR (DMSO, 400 MHz): δ8.43 (m, 1H, NH), 7.87-7.43 (m, 6H,ArH), 6.65 (s, 1H, ═CH), 5.52 (d, J=6.4 Hz, 1H, OH), 4.48-2.75 (m, 15H).LC-MS: (ESI, m/z)=526 [M+H]⁺

Example 361N2-(2-chloro-5-((S)-2-hydroxypropylcarbamoyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide361

To the mixture of3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (2.5 g, 5.07 mmol) in THF (50 mL) was added EDCI (1.94 g, 10.14mmol), HOBt (1.03 g, 7.61 mmol), DIPEA (5 mL) and(S)-1-amino-propan-2-ol (0.57 g, 7.61 mmol) by sequence under nitrogenatmosphere at room temperature. The reaction mixture was stirredovernight, diluted with water. The resulting precipitate was washed withwater and EtOAc to give8-bromo-N-(2-chloro-5-((S)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(2.0 g, yield 72%). ¹H NMR (DMSO-d6, 400 MHz): δ8.62-6.60 (m, 8H, NH,ArH), 4.77 (d, J=4.8 Hz, 1H, OH), 4.18 (br s, 2H, CH₂), 3.79-3.75 (m,1H, CH), 3.31 (s, 3H, NCH₃), 3.19 (br s, 2H, CH₂), 2.94 (br s, 2H, CH₂),1.05 (d, J=6.0 Hz, 3H, CH₃). LC-MS: (ESI, m/z)=549 [M+H]⁺

A suspension of8-bromo-N-(2-chloro-5-((S)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(500 mg, 1.00 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), Xantphos (58 mg, 0.01mmol), MeNH₂.HCl (101 mg, 1.50 mmol) and Na₂CO₃ (318 mg, 3.00 mmol) intoluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere ofCO from balloon overnight. Then it was filtrated and concentrated,diluted with water. The resulting precipitate was washed with water andDCM, dried to give 361 (158.9 mg, yield 30%). ¹H NMR (DMSO-d6, 400 MHz):δ8.63-7.43 (m, 8H, NH, ArH), 6.62 (s, 1H, ═CH), 4.77 (d, J=4.0 Hz, 1H,OH), 4.18 (br s, 2H, CH₂), 3.78-3.76 (m, 1H, CH), 3.32 (s, 3H, NCH₃),3.24 (br s, 2H, CH₂), 2.98 (br s, 2H, CH₂), 2.75 (d, J=4.4 Hz, 3H,NCH₃)., 1.06 (d, J=6.4 Hz, 3H, CH₃). LC-MS: (ESI, m/z)=528 [M+H]⁺, 550[M+Na]⁺

Example 3621-(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidin-1-yl)-ethanone362

Compound 435 (150 mg, 0.3 mmol) was dissolved in THF, and DIPEA wasadded. Acetyl chloride was added dropwise into the solution. After theaddition, the reaction mixture was further stirred at room temperaturefor 12 h. The reaction mixture was concentrated in vacuo, and dissolvedin DCM. The organic layer was washed by water, dried by Na₂SO₄,concentrated in vacuo, and purified by prep. TLC (DCM/EtOAc=10:1) togive 362 (15 mg, 10%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.36 (s, 1H),8.02-7.92 (m, 1H), 7.83 (t, J=8.8 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.31(s, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 4.38-4.35 (m,2H), 4.25-4.16 (m, 4H), 3.74 (s, 1H), 3.24 (s, 2H), 1.89 (s, 3H).ESI-MS: m/z=495 [M+H⁺]

Example 363{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(1-methanesulfonyl-azetidin-3-yl)-amine363

Azetidin-3-yl-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-amine(452 mg, 1.0 mmol), Methanesulfonyl chloride (136 mg, 1.2 mmol), DIPEA(260 mg, 2.0 mmol) was dissolved in THF (10 mL). The reaction mixturewas stirred at room temperature (r.t.) for 1 hour. LC-MS indicated thereaction was completed. To the reaction mixture was added 20 mL ofwater, the mixture was extracted with dichloromethane. The organic layerwas dried over anhydrous sodium sulfate, and concentrated to dryness.The crude was purified by pre-HPLC to afford 363 (57.2 mg, yield: 11%).¹HNMR (DMSO-d₆, 400 MHz): δ 9.50 (s, 1H), 8.72 (s, 1H), 8.31 (s, 1H),7.97-7.91 (m, 2H), 7.77-7.72 (m, 2H), 7.48-7.43 (m, 2H), 7.15 (s, 1H),6.99 (s, 1H), 6.72 (d, J=4.4 Hz, 1H), 4.31 (s, 2H), 3.86 (s, 2H), 3.33(s, 2H), 3.15 (s, 2H), 2.75 (s, 6H). ESI-MS: m/z=531 [M+H⁺]

Example 364N-(1-Acetyl-azetidin-3-yl)-N-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-acetamide364

Compound 435 (150 mg, 0.3 mmol) was dissolved in THF, and DIPEA wasadded. Acetyl chloride was added dropwise into the solution. After theaddition, the reaction mixture was further stirred at room temperaturefor 12 h. The reaction mixture was concentrated in vacuo, and dissolvedin DCM. The organic layer was washed by water, dried by Na₂SO₄,concentrated in vacuo, and purified by prep. TLC (DCM/EtOAc=10:1) togive 364 (20 mg, yield: 12%). ¹HNMR (DMSO-d₆, 400 MHz): δ8.02 (s, 1H),7.74-7.72 (m, 1H), 7.41-7.37 (m, 2H), 7.26 (t, J=8.8 Hz, 1H), 7.18 (d,J=8.4 Hz, 1H), 4.99 (m, 1H), 4.28-4.24 (m, 4H), 4.03 (t, J=8.4 Hz, 1H),3.96 (t, J=9.6 Hz, 1H), 3.56-3.53 (m, 1H), 3.08 (s, 1H), 3.24 (s 2H),1.91 (s, 3H), 1.58 (s, 3H). ESI-MS: m/z=536 [M+H⁺]

Example 365 4,5-Dihydro-6-oxa-1-thia-benzo[e]azulene-2,8-dicarboxylicacid2-{[2-chloro-5-((R)-2-hydroxy-propylcarbamoyl)-phenyl]-methyl-amide}8-methylamide 365

To a mixture of3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and(R)-1-amino-propan-2-ol (0.69 g, 9.13 mmol) by sequence under nitrogenatmosphere at room temperature. The reaction mixture was stirredovernight, diluted with water. The resulting precipitate was washed withwater and EtOAc to give8-bromo-N-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(2.7 g, yield 81%). ¹H NMR (DMSO-d6, 400 MHz): δ8.62 (t, J=5.2 Hz, 1H,NH), 8.11-6.11 (m, 7H, ArH), 4.77 (d, J=4.4 Hz, 1H, OH), 4.18 (br s, 2H,CH₂), 3.81-3.75 (m, 1H, CH), 3.32 (s, 3H, NCH₃), 3.19 (br s, 2H, CH₂),2.94 (br s, 2H, CH₂), 1.05 (d, J=6.0 Hz, 3H, CH₃). LC-MS: (ESI, m/z)=549[M+H]⁺

The suspension of8-bromo-N-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(500 mg, 1.00 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), Xantphos (58 mg, 0.01mmol), MeNH₂.HCl (101 mg, 1.50 mmol) and Na₂CO₃ (318 mg, 3.00 mmol) intoluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere ofCO from balloon overnight. Then it was filtrated and concentrated,diluted with water. The resulting precipitate was washed with water andDCM, the crude product was purified by preparative HPLC to give 365(52.3 mg, yield 10%). ¹H NMR (DMSO-d6, 400 MHz): δ8.63-7.43 (m, 8H, NH,ArH), 6.61 (s, 1H, ═CH), 4.78 (brs, 1H, OH), 4.20 (brs, 2H, CH₂),3.80-3.79 (m, 1H, CH), 3.35-2.66 (m, 10H, CH₃, CH₂), 2.98 (brs, 2H,CH₂), 2.75 (d, J=4.4 Hz, 3H, NCH₃)., 1.07-0.97 (m, 3H, CH₃). LC-MS:(ESI, m/z)=528 [M+H]⁺

Example 3661-(4-{2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-2-methyl-propan-2-ol366

Similarly to as described in General Procedure C,5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazol-3-ylaminewas reacted with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol.Purification of the crude reaction mixture by reverse phase HPLC gave366. LCMS: 536.1.

Example 3671-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol367

Similar to as described in General Procedure C,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 was reacted with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol.Purification of the crude reaction mixture by reverse phase HPLC gave367. LCMS: 451.1

Example 3681-{4-[2-(5-Amino-2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol368

Similar to as described in General Procedure C,5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylaminewas reacted with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol.Purification of the crude reaction mixture by reverse phase HPLC gave368. LCMS: 466.2.

Example 3699-[1-((R)-2-Hydroxy-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 369

Following the procedure for 277,9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxy-ethyl)-isopropyl-amide (418 mg, 1.02 mmol) and(R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazol-1-yl)propan-2-ol(307.4 mg, 1.22 mmol) were reacted to give 369 (44.8 mg, 10% yield, M+1457.1).

Example 3705-(8-Azetidin-3-yl-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole370

Following the procedure for 419,5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-isopropyl-1H-1,2,4-triazole(313.4 mg, 0.803 mmol) was dissolved in N,N-dimethyacetamide and purgedwith nitrogen. Added[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (32.8 mg, 0.04 mmol) and copper(I)iodide (15.3 mg,0.08 mmol). Bubbled in nitrogen for 10 minutes. Added(1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (279.8 mg, 0.80mmol) in 2.8 mL DMA. Heated at 80° C. overnight. Complete reaction wasconfirmed by LCMS. Diluted reaction mixture with 1 M HCl and extractedtert-butyl3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylatewith ethyl acetate. Dried over magnesium sulfate and concentrated invacuo. Purified by flash chromatography (0 to 50% ethyl acetate inhexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours.Complete deprotection was confirmed by LCMS. Concentrated in vacuopurified by HPLC to give 370 (33.3 mg, 11% yield, M=1 367.1)

Example 3712-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin-1-yl}-acetamide371

Following the procedure of 319,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand bromoacetamide were reacted in DMF to give 371 (111 mg, 53%). LCMS:R_(T)=6.96 min, [M+H]⁺=425. ¹H NMR δ (ppm) (CDCl₃): 8.31 (1H, d, J=2.35Hz), 7.90 (1H, s), 7.17 (1H, dd, J=8.28, 2.36 Hz), 7.03 (1H, d, J=8.26Hz), 7.01-6.85 (1H, m), 5.91-5.83 (1H, m), 5.41 (1H, s), 4.37 (2H, t,J=5.06 Hz), 3.89 (2H, t, J=7.36 Hz), 3.81-3.73 (1H, m), 3.43-3.34 (4H,m), 3.22 (2H, s), 1.63 (6H, d, J=6.65 Hz)

Example 3729-[1-(2,4-Difluoro-benzyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene372

A mixture of9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.18 g, 0.49 mmol), 2,4-difluorobenzaldehyde (64 μL, 0.59 mmol) and 4 Åmolecular sieves in chloroform (7 mL) was heated to reflux for 3.5hours. After cooling sodium triacetoxyborohydride (0.50 g, 2.36 mmol)was added and the mixture was stirred at RT overnight. Aqueous saturatedsodium bicarbonate solution was added and the phases were separated. Theaqueous phase was extracted with 10% MeOH/DCM (×4) and the combinedorganic phase was dried (Na₂SO₄) and concentrated in vacuo. Theresultant residue was purified by flash chromatography (SiO₂, 50-100%EtOAc in cyclohexane) to give 372 (122 mg, 50%). LCMS: R_(T)=8.65 min,[M+H]⁺=494. ¹H NMR δ (ppm) (CDCl₃): 8.31 (1H, d, J=2.33 Hz), 7.90 (1H,s), 7.33 (1H, q, J=7.71 Hz), 7.14 (1H, dd, J=8.27, 2.33 Hz), 7.01 (1H,d, J=8.26 Hz), 6.86-6.74 (2H, m), 5.94-5.84 (1H, m), 4.37 (2H, t, J=5.06Hz), 3.83-3.73 (3H, m), 3.68 (2H, s), 3.39 (2H, t, J=5.07 Hz), 3.29-3.23(2H, m), 1.61 (6H, d, J=6.65 Hz)

Example 3739-[1-(2-Chloro-benzyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene373

Following the procedure for 372, a mixture of9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.18 g, 0.49 mmol) and 2-chlorobenzaldehyde gave 373 (123 mg, 51%).LCMS: R_(T)=8.80 min, [M+H]⁺=492/494. ¹H NMR δ (ppm) (CDCl₃): 8.34 (1H,d, J=2.34 Hz), 7.90 (1H, s), 7.43 (1H, d, J=7.55 Hz), 7.33 (1H, dd,J=7.76, 1.47 Hz), 7.24-7.13 (3H, m), 7.01 (1H, d, J=8.25 Hz), 5.95-5.82(1H, m), 4.40-4.34 (2H, m), 3.90-3.83 (2H, m), 3.85-3.76 (3H, m),3.42-3.36 (2H, m), 3.35-3.28 (2H, m), 1.60 (6H, d, J=6.65 Hz)

Example 3742-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene374

Following the procedure for 375,3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester was treated with acid. The crude product waspurified by trituration with EtOAc containing a few drops of MeOH togive 374 as a pale brown solid (5.8 mg, 34%). LCMS: R_(T)=7.68 min,[M+H]⁺=382. ¹H NMR δ (ppm) (DMSO-d6): 9.11 (2H, s), 8.27 (1H, d, J=8.21Hz), 8.05 (1H, s), 7.14 (1H, dd, J=8.26, 1.86 Hz), 7.03 (1H, d, J=1.80Hz), 5.81-5.71 (1H, m), 4.35-4.29 (2H, m), 3.57 (1H, dd, J=11.24, 8.03Hz), 3.45-3.31 (4H, m), 3.23-3.12 (1H, m), 3.11-2.99 (1H, m), 2.37-2.27(1H, m), 1.97-1.85 (1H, m), 1.49 (6H, d, J=6.59 Hz)

Example 3752-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene375

Following the procedure for 235,4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester and a 1:3 ratio of TFA:DCM gave 375 isolated as abrown solid (2.18 g, 87%). LCMS: R_(T)=2.90 min, [M+H]⁺=396

Alternatively, to a suspension of4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (470 mg, 0.95 mmol) in MeOH (10 mL) was added 1MHCl in ether (1.9 mL, 1.90 mmol). The reaction mixture was stirred for18 hours then the volatiles were removed in vacuo. The resultant residuewas stirred in diethyl ether (20 mL) for 20 minutes then the solid wasfiltered off and further triturated with a mixture of MeOH and ether togive 375 as a white solid (104 mg, 28%). LCMS: R_(T)=7.82 min,[M+H]⁺=396. ¹H NMR δ (ppm) (DMSO-d6): 8.86 (2H, s), 8.26 (1H, d, J=8.20Hz), 8.05 (1H, s), 7.03 (1H, dd, J=8.26, 1.83 Hz), 6.87 (1H, d, J=1.78Hz), 5.81-5.71 (1H, m), 4.31 (2H, t, J=5.01 Hz), 3.37 (2H, t, J=5.01Hz), 3.30 (2H, d, J=12.46 Hz), 2.93 (2H, d, J=11.52 Hz), 2.84-2.75 (1H,m), 1.92-1.75 (4H, m), 1.49 (6H, d, J=6.59 Hz)

Example 3762-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin-1-yl}-ethanol376

A solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(110 mg, 0.22 mmol) in MeOH (3 mL) and DCM (3 mL) was treated with 4NHCl/dioxan (2 mL, 8 mmol) and the mixture left to stand for 3 hours thenconcentrated in vacuo. The resultant residue was triturated with diethylether and dried under vacuum. Further purification by flashchromatography (SiO₂, 0-10% 2N NH₃/MeOH in DCM) gave 376 (29 mg, 32%).LCMS: R_(T)=6.96 min, [M+H]⁺=412. ¹H NMR δ (ppm) (CDCl₃): 8.31 (1H, d,J=2.34 Hz), 7.90 (1H, s), 7.15 (1H, dd, J=8.27, 2.35 Hz), 7.01 (1H, d,J=8.26 Hz), 5.94-5.84 (1H, m), 4.40-4.34 (2H, m), 3.89-3.83 (2H, m),3.84-3.72 (1H, m), 3.59-3.54 (2H, m), 3.41-3.36 (2H, m), 3.28-3.21 (2H,m), 2.71-2.66 (2H, m), 1.62 (6H, d, J=6.65 Hz). 1 Exchangeable protonnot seen

Example 3771-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propan-2-ol377

Lithium perchlorate (52 mg, 0.49 mmol) was added to THF (5 mL) followedby 1,2-epoxy-2-methylpropane (0.43 mL, 4.9 mmol) and the mixture wasstirred for 10-15 minutes giving a clear solution.9-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.18 g, 0.49 mmol) was added and the reaction mixture was stirred for72 hours then concentrated in vacuo. The resultant residue was purifiedby flash chromatography (SiO₂, 0-10% MeOH in EtOAc) and the resultingsolid extracted several times with ether. The ether extracts wereconcentrated in vacuo to give 377 (77 mg, 97%). LCMS: R_(T)=7.45 min,[M+H]⁺=440. ¹H NMR δ (ppm) (CDCl₃): 8.28 (1H, d, J=2.34 Hz), 7.90 (1H,s), 7.16 (1H, dd, J=8.29, 2.35 Hz), 7.02 (1H, d, J=8.27 Hz), 5.93-5.83(1H, m), 4.40-4.34 (2H, m), 4.04-3.95 (2H, m), 3.89-3.79 (1H, m),3.46-3.36 (4H, m), 2.55 (2H, s), 1.63 (6H, d, J=6.64 Hz), 1.15 (6H, s).1 Exchangeable proton not seen

Example 378(S)-2-Hydroxy-1-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-piperidin-1-yl}-propan-1-one378

Following the procedure for 358, using L-(+)-lactic acid instead ofD-(−)-lactic acid to give 378 isolated as a white solid (126 mg, 63%).LCMS: R_(T)=11.58 min, [M+H]⁺=468. ¹H NMR δ (ppm) (DMSO-d6): 8.19 (1H,d, J=2.29 Hz), 8.06 (1H, s), 7.14 (1H, d, J=8.33 Hz), 6.96 (1H, d,J=8.24 Hz), 5.79-5.69 (1H, m), 4.80 (1H, s), 4.51-4.37 (2H, m),4.33-4.27 (2H, m), 4.16-3.98 (1H, m), 3.41-3.35 (2H, m), 3.16-3.02 (1H,m), 2.84-2.75 (1H, m), 2.71-2.59 (1H, m), 1.84 (2H, d, J=12.53 Hz),1.57-1.47 (8H, m), 1.20-1.14 (3H, m)

Example 3802-Methyl-1-(4-{2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propan-2-ol380

Following the procedure for 114,8-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 380. MS(ESI+) 506.2. ¹H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3,1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.44 (dd, J=8.3, 1.8,1H), 7.32 (d, J=1.7, 1H), 5.47-5.35 (m, 1H), 4.72 (s, 1H), 4.39 (t,J=4.9, 2H), 4.04 (s, 2H), 3.45 (t, J=5.0, 2H), 3.05-2.95 (m, 2H), 2.28(s, 3H), 2.22-1.98 (m, 6H), 1.10 (s, 6H)

Example 381(S)-1-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propan-2-ol381

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with(S)-1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 381. MS(ESI+) 477.1

Example 3828-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid cyclohexyl-(2-dimethylamino-ethyl)-amide 382

To a well stirred solution of8-[2-methyl-1-(1H-pyrazol-1-yl)propan-2-ol)]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (0.211 mg, 0.546 mmol) in DMF (1.7 mL) at room temperature wasadded N1-cyclohexyl-N2,N2-dimethylethane-1,2-diamine (0.19 mmol),followed by the addition of DIPEA (0.46 ml, 2.7 mmol). Finally, HATU(0.230 grams, 0.600 mmol) was added and the reaction mixture was heatedas a slurry at room temperature for 90 minutes. The reaction mixture wasconc. in vacuo and taken into a large volume of EtOAc and the org. waswashed with dilute aqueous bicarbonate, water and then saline and dried(Na2SO4), then concentrated to a residue. The crude material waspurified by preparative RP-HPLC to give 382 as a lyophilized solid. MS:(ESI+)=558.3

Example 383N2-(2-chloro-5-(2-hydroxyethyl)(methyl)carbamoyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide383

To a mixture of3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and 2-(methylamino)ethanol(0.69 g, 9.13 mmol) by sequence under nitrogen atmosphere at roomtemperature. The reaction mixture was stirred overnight, diluted withwater. The resulting precipitate was washed with water and EtOAc to give8-bromo-N-(2-chloro-5-((2-hydroxyethyl)(methyl)carbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(2.8 g, yield: 87%). LC-MS: (ESI, m/z)=549 [M+H]⁺

A suspension of8-bromo-N-(2-chloro-5-((2-hydroxyethyl)(methyl)carbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(400 mg, 0.76 mmol), Pd(OAc)₂ (10 mg, 0.045 mmol), Xantphos (44 mg,0.076 mmol), MeNH₂.HCl (77 mg, 1.14 mmol) and Na₂CO₃ (242 mg, 2.28 mmol)in toluene (5 mL) was heated at 80° C. under atmosphere of CO fromballoon overnight. Then it was filtrated and concentrated, the crudeproduct was purified by column (EtOAc:MeOH=10:1) to afford 383 (87.2 mg,yield: 22%). ¹HNMR (DMSO-d6, 400 MHz): δ8.45 (d, J=4.4 Hz, 1H),7.72-7.43 (m, 6H), 6.73 (s, 1H), 4.89-4.76 (m, 1H), 4.20-4.04 (m, 2H),3.60-2.66 (m, 15H). LC-MS: (ESI, m/z)=528 [M+H]⁺

Example 384N2-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide384

A suspension of8-bromo-N-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(400 mg, 0.73 mmol), Pd(OAc)₂ (8 mg, 0.037 mmol), Xantphos (42 mg, 0.073mmol), MeSO₂(CH₂)₂NH₂.HCl (175 mg, 1.095 mmol) and Na₂CO₃ (232 mg, 2.19mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. underatmosphere of CO from balloon for overnight. Then it was filtrated andconcentrated, the crude product was purified by flash columnchromatography on silica gel (DCM:MeOH=20:1 as eluted solvent) to give awhite solid which was washed with MeOH and dried to give 384 (206.7 mg,yield 46%). ¹H NMR (DMSO, 400 MHz): δ8.74 (t, J=5.6 Hz, 1H, NH),7.87-6.61 (m, 7H, ArH), 5.75 (d, J=6.0 Hz, 1H, OH), 4.48-2.99 (m, 19H).LC-MS: (ESI, m/z)=618 [M+H]⁺

Example 385N2-(2-chloro-5-(2-hydroxyethylcarbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide385

A suspension of2-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzamido)ethylacetate (400 mg, 0.69 mmol), Pd(OAc)₂ (10 mg, 0.045 mmol), Xantphos (40mg, 0.069 mmol), MeSO₂CH₂CH₂NH₂.HCl (165 mg, 1.04 mmol) and Na₂CO₃ (219mg, 2.07 mmol) in toluene (5 mL) was heated at 80° C. under atmosphereof CO from balloon overnight. Then it was filtrated and concentrated,the crude product was purified by column (EtOAc:MeOH=10:1) to afford 385(76.8 mg, yield: 18%). ¹HNMR (DMSO-d6, 400 MHz): δ8.70 (t, J=5.6 Hz,1H), 8.61 (d, J=5.6 Hz, 1H), 8.07-7.41 (m, 6H), 6.57 (s, 1H), 4.72 (s,1H), 4.71 (t, J=5.6 Hz, 1H), 3.63-2.95 (m, 16H). LC-MS: (ESI, m/z)=606[M+H]⁺

Example 386N2-(2-chloro-5-(2-hydroxyethyl)(methyl)carbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide386

A suspension of8-bromo-N-(2-chloro-5-((2-hydroxyethyl)(methyl)carbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(400 mg, 0.76 mmol), Pd(OAc)₂ (10 mg, 0.045 mmol), Xantphos (44 mg,0.076 mmol), MeSO₂CH₂CH₂NH₂.HCl (181 mg, 1.14 mmol) and Na₂CO₃ (242 mg,2.28 mmol) in toluene (5 mL) was heated at 80° C. under atmosphere of COfrom balloon overnight. Then it was filtrated and concentrated, thecrude product was purified by column (EtOAc:MeOH=10:1) to afford 386(56.9 mg, yield: 12%). ¹HNMR (DMSO-d6, 400 MHz): δ8.71 (t, J=5.6 Hz,1H), 7.71-7.41 (m, 6H), 6.70 (s, 1H), 4.83-4.73 (m, 1H), 4.18-4.15 (m,2H), 3.64-2.88 (m, 19H). LC-MS: (ESI, m/z)=620 [M+H]⁺

Example 387N2-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide387

A suspension of8-bromo-N-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(500 mg, 0.91 mmol), Pd(OAc)₂ (10 mg, 0.045 mmol), Xantphos (53 mg,0.091 mmol), MeSO₂(CH₂)₂NH₂.HCl (218 mg, 1.36 mmol) and Na₂CO₃ (289 mg,2.73 mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. underatmosphere of CO from balloon overnight. Then it was filtrated andconcentrated, the crude product was purified by pre-TLC (DCM:MeOH=10:1as eluted solvent) to give 387 (101.5 mg, yield 18%). ¹H NMR (DMSO-d6,400 MHz): δ8.73 (s, 1H, NH), 8.60 (s, 1H, NH), 8.12-7.45 (m, 6H, ArH),6.61 (s, 1H, ═CH), 4.76 (d, J=4.8 Hz, 1H, OH), 4.20 (br s, 2H, CH₂),3.80-3.77 (m, 1H, CH), 3.67-2.98 (m, 14H, CH₃, CH₂), 1.06 (t, J=5.2 Hz,3H, CH₃). LC-MS: (ESI, m/z)=542 [M+Na]⁺

Example 388(S)-1-(4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazin-1-yl)-2-hydroxy-propan-1-one388

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperazin-1-yl-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(150 mg, 0.32 mmol), HATU (244 mg, 0.64 mmol) and DIPEA (165 mg, 1.28mmol) was dissolved in DMF (5 mL). The reaction mixture was stirred atroom temperature for 2 hours. LC-MS showed the reaction is completed. Tothe reaction was added water (15 mL), some solid appeared. It wasfiltered, and the solid was collected and used to the next step directly(140 mg yield: 60%). The above residue (140 mg, 0.21 mmol) was dissolvedin 5 mL of THF, and then NaOH (18 mg, 0.42 mmol) in 5 mL of water wasadded dropwise at 0° C. The reaction mixture was allowed to warm up toroom temperature slowly and stirred at room temperature for 1 hour.Evaporated to remove most of THF, extracted with dichloromethane, driedover anhydrous sodium sulfate, concentrated to dryness to afford 388 (45mg, yield: 40%). ¹H NMR (CDCl₃, 400 MHz): δ8.08 (s, 1H), 7.54-7.51 (m,1H), 7.24-7.02 (m, 4H), 6.54-6.53 (d, J=7.2 Hz, 1H), 4.55-4.51 (m, 1H),4.24-4.22 (m, 2H), 3.82-3.76 (m, 3H), 3.52-3.50 (m, 4H), 3.43-3.41 (m,2H), 3.11-3.08 (m, 2H), 1.40-1.38 (m, 6H). ESI-MS: m/z=539 [M+H⁺]

Example 389(S)-1-(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidin-1-yl)-2-hydroxy-propan-1-one389

Compound 435 (150 mg, 0.31 mmol), (S)-2-(benzyloxycarbonyloxy)propanoicacid, EDCI (127 mg, 0.61 mmol), HOBt (83 mg, 0.61 mmol) and DIPEA (240mg, 1.86 mmol) was dissolved in DMF (10 mL). The reaction mixture wasstirred at about −5° C. for 1 hour. LC-MS indicated the reaction wascompleted. To the reaction mixture was added 20 mL of water, the mixturewas extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate, concentrated to dryness, and purified bypre-TLC to afford 110 mg of Cbz protected 389.

The above Cbz protected 389 intermediate (110 mg, 0.17 mmol) wasdissolved in THF (5 mL), then NaOH (13 mg, 0.34 mmol) in 5 mL of waterwas added dropwise at 0° C. The reaction mixture was allowed to warm upto room temperature slowly and stirred at room temperature for 1 hour.It was evaporated to remove most of THF, extracted with dichloromethane,dried over anhydrous sodium sulfate, concentrated to dryness andpurified by pre-HPLC to afford 44 mg of 389 (yield=50%). ¹H NMR (CDCl₃,400 MHz): δ8.02 (s, 1H), 7.50-7.45 (m, 1H), 7.09-6.88 (m, 4H), 6.28-6.25(m, 1H), 4.56-4.41 (m, 5H), 4.19-4.17 (m, 2H), 3.92-3.91 (m, 2H),3.55-3.48 (m, 1H), 3.06-3.02 (m, 2H), 1.35-1.25 (m, 3H). LC-MS (ESI):m/z=525 [M+H]⁺

Example 3909-[(3R,5S)-4-(2,2-Difluoro-ethyl)-3,5-dimethyl-piperazin-1-yl]-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene390

Compound 391 (120 mg, 0.21 mmol) was dissolved in tetrahydrofuran (5mL), borane/dimethylsulfane (10 mol/L, 2 mL) was added dropwise at 0°C., 30 min later the temperature of the mixture was allowed to warm toabout 25° C. and stirred for 1 hour. To the reaction mixture was added15 mL of methanol slowly, then 5 mL of conc. HCl was added followed, themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated to remove methanol and dimethylsulfane. The residue wasdissolved in dichloromethane, washed with water, the organic layer wasconcentrated to dryness and the crude was purified by pre-TLC to afford65 mg of 390. Yield: 56%. ¹H NMR (CDCl₃, 400 MHz): δ8.01 (s, 1H),7.49-7.48 (m, 1H), 7.09-6.98 (m, 4H), 6.45-6.43 (d, J=8.8 Hz, 1H), 5.92(t, J=60.0 Hz, 1H), 4.18-4.16 (m, 2H), 3.84-3.81 (m, 2H), 3.07-3.05 (m,2H), 2.98-2.90 (m, 2H), 2.70-2.67 (m, 2H), 2.53-2.50 (m, 2H), 1.12-1.11(m, 6H). LC-MS (ESI): m/z=559 [M+H]⁺

Example 3911-((2R,6S)-4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-2,6-dimethyl-piperazin-1-yl)-2,2-difluoro-ethanone391

2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(200 mg, 0.4 mmol) was dissolved in 10 mL of THF. Then the mixture wasstirred at about −15° C. for 5 min, pyridine (1 mL) was added dropwisefollowed. 5 min later, difluoro-acetyl chloride (excess) was bubbled into the reaction mixture for about 2 min. The temperature of the reactionwas allowed to warm to ambient temperature slowly and stirred for about1 hour. To the reaction mixture was added saturated sodium bicarbonateand extracted with DCM, the organic phase was dried over anhydroussodium sulfate and concentrated to dryness to give 391. HPLC indicatedthe purity is above 95%. ¹H NMR (CDCl₃, 400 MHz): δ8.04 (s, 1H),7.52-7.47 (m, 1H), 7.19-7.00 (m, 4H), 6.50-6.48 (m, 1H), 4.62-4.60 (m,1H), 4.23-4.16 (m, 4H), 3.91-3.88 (m, 1H), 3.07-2.89 (m, 4H), 1.36-1.31(m, 6H). LC-MS (ESI): m/z=573 [M+H]⁺

Example 392N-(2-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-ethyl)-acetamide392

A mixture of9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), Pd₂(dba)₃ (66 mg, 0.072 mmol),N-(2-Amino-ethyl)-acetamide (147 mg, 1.44 mmol), Xphos (69 mg, 0.144mmol) in dioxane (2 mL) was added to a MW tube. The mixture was bubbledN₂ for about 2 min, ^(t)BuONa (142 mg, 1.44 mmol), was added followedand bubbled N₂ for another 2 min. The mixture was stirred at 120° C. for45 min under the irradiation of microwave. The mixture was filteredthough a ceilite, the filtrate was concentrated to dryness and purifiedby pre-TLC (pure EtOAc) and pre-HPLC to afford 56 mg of 392.(yield=16%). ¹H NMR (CDCl₃, 400 MHz): δ8.02 (s, 1H), 7.50-7.44 (m, 1H),7.19-6.99 (m, 4H), 6.25-6.17 (m, 2H), 4.55 (s, 1H), 4.18-4.16 (m, 2H),3.46-3.40 (m, 2H), 3.06-3.04 (m, 2H), 1.80-1.79 (m, 1H). ESI-MS: m/z=483[M+H⁺]

Example 3931,1-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethylamine393

Following the procedure for 114,8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with{1,1-Dimethyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-carbamicacid tert-butyl ester to give[1,1-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-carbamicacid tert-butyl ester. MS(ESI+) 590.2.

To a round bottom flask containing[1,1-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-carbamicacid tert-butyl ester (0.175 g, 0.000297 mol) in methylene chloride (1.1mL, 0.017 mol) was added trifluoroacetic acid (1.3 mL, 0.017 mol). Thesolution was stirred at room temperature until CO₂ evolution stopped (30minutes). The solvent was removed in vacuo and purified by reverse-phaseHPLC to give 393 (21.8 mg) as a white solid. MS(ESI+) 490.1. ¹H NMR (400MHz, DMSO) δ 8.37 (d, J=9.7, 1H), 8.29 (s, 1H), 8.26 (d, J=8.3, 1H),7.98 (s, 1H), 7.49 (dd, J=8.3, 1.7, 1H), 7.37 (d, J=1.7, 1H), 5.86 (q,J=8.7, 2H), 4.39 (t, J=5.0, 2H), 3.47 (t, J=5.0, 2H), 2.86 (s, 2H), 1.50(s, 6H).

Example 3942-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidine-1-sulfonyl}-ethanol394

To a solution of9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.20 g, 0.54 mmol) in dry THF (20 mL) at 0° C. was added2-chloroethanesulfonyl chloride (65 μL, 0.6 mmol) and the reactionmixture was stirred at RT for 18 hours. The reaction mixture was cooledto 0° C. and a further 2-chloroethanesulfonyl chloride (1304) was addedand the reaction mixture was stirred at RT for 18 hours. An aqueoussodium hydroxide solution (8M, 3.38 mL, 27 mmol) was added and themixture was heated at 40° C. for 18 hours then concentrated in vacuo.The resultant residue was extracted several times with 10% MeOH in DCMand the combined extracts concentrated in vacuo. The residue waspurified by flash chromatography (SiO₂, 0-20% MeOH in DCM) followed bypreparative HPLC (Gemini C₁₈ column, gradient 5-95% MeOH in H₂O+0.1%HCO₂H) to give 394 (58 mg, 23%). LCMS: R_(T)=8.45 min, [M+H]⁺=476. ¹HNMR δ (ppm) (DMSO-d6, 80° C.): 8.22 (1H, d, J=2.31 Hz), 8.01 (1H, s),7.33 (1H, dd, J=8.34, 2.39 Hz), 7.08 (1H, d, J=8.32 Hz), 5.81-5.73 (1H,m), 4.53 (2H, s), 4.37 (2H, t, J=5.09 Hz), 4.22 (3H, s), 3.57 (2H, t,J=6.26 Hz), 3.43 (2H, t, J=5.09 Hz), 2.79 (2H, t, J=6.37 Hz), 1.59 (6H,d, J=6.61 Hz). 1 Exchangeable proton not observed

Example 3952-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonyl-piperidin-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene395

To a suspension of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene375 hydrochloride salt (141 mg, 0.33 mmol) in DCM (3.3 mL) was addedtriethylamine (0.16 mL, 1.14 mmol). The reaction mixture was cooled to0° C. then methanesulfonyl chloride (30 μL, 0.39 mmol) was added and thereaction mixture was stirred at RT for 18 hours. The reaction mixturewas cooled to 0° C. and a further triethylamine (45 μL) andmethanesulfonyl chloride (30 μL) were added and the reaction mixture wasstirred at 0° C. for 30 minutes. Water was added and the phases wereseparated. The aqueous layer was extracted with DCM (×2) and thecombined organic extracts were washed with an aqueous 10% citric acidsolution, followed by an aqueous saturated sodium bicarbonate solutionand then brine, dried (Na₂SO₄) and concentrated in vacuo. The resultantresidue was purified by flash chromatography (SiO₂, 0-20% EtOAc in DCM).The resulting solid was suspended in cyclohexane and collected byfiltration to give 395 as a white solid (78 mg, 50%). LCMS: R_(T)=11.69min, [M+H]⁺=474. ¹H NMR δ (ppm) (CDCl₃): 8.31 (1H, d, J=8.19 Hz), 7.90(1H, s), 7.01 (1H, dd, J=8.23, 1.88 Hz), 6.90 (1H, d, J=1.84 Hz),5.93-5.85 (1H, m), 4.39 (2H, t, J=5.03 Hz), 3.93 (2H, d, J=11.84 Hz),3.39 (2H, t, J=5.04 Hz), 2.81-2.70 (5H, m), 2.60 (1H, tt, J=12.04, 3.68Hz), 1.97 (2H, d, J=13.31 Hz), 1.89-1.76 (2H, m), 1.61 (6H, d, J=6.63Hz)

Example 3962-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonyl-pyrrolidin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene396

Following the procedure for 395,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenehydrochloride salt and methanesulfonyl chloride gave 396 isolated as apale orange solid (28 mg, 48%). LCMS: R_(T)=11.27 min, [M+H]⁺=460. ¹HNMR δ (ppm) (CDCl₃): 8.33 (1H, d, J=8.21 Hz), 7.90 (1H, s), 7.05 (1H,dd, J=8.24, 1.91 Hz), 6.94 (1H, d, J=1.87 Hz), 5.93-5.83 (1H, m),4.42-4.36 (2H, m), 3.79 (1H, dd, J=9.53, 7.31 Hz), 3.61 (1H, ddd,J=9.97, 8.27, 3.30 Hz), 3.50-3.31 (5H, m), 2.86 (3H, s), 2.41-2.32 (1H,m), 2.15-2.03 (1H, m), 1.61 (6H, d, J=6.63 Hz)

Example 3972-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanone397

Following the procedure for 318,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 31 and glycolic acid were reacted. Purification by reversephase preparative HPLC (Gemini C₁₈ column, gradient 5-98% MeOH inH₂O+0.1% HCO₂H) gave 397 as a white solid (46 mg, 27%). LCMS:R_(T)=10.33 min, [M+H]⁺=426. ¹H NMR δ (ppm) (DMSO-d6): 8.30 (1H, d,J=8.20 Hz), 8.05 (1H, s), 7.20-7.15 (1H, m), 7.01 (1H, d, J=1.82 Hz),5.82-5.72 (1H, m), 4.88-4.81 (1H, m), 4.55-4.46 (1H, m), 4.34-4.29 (2H,m), 4.30-4.17 (1H, m), 4.16 (1H, dd, J=9.24, 5.41 Hz), 3.90 (2H, d,J=5.77 Hz), 3.89-3.77 (2H, m), 3.41-3.35 (2H, m), 1.49 (6H, d, J=6.59Hz)

Example 398(R)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin-1-yl}-propan-1-one398

Following the procedure for 318,9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand sodium D-lactate in DMF were reacted. After purification by flashchromatography a lactate-ester by-product of the title compound waspresent. The mixture (0.11 g, 0.2 mmol) was dissolved in 1,4-dioxan (2mL) and treated with 1M aqueous sodium hydroxide solution (0.2 mL, 0.2mmol). The reaction mixture was stirred for 2 hours then diluted withEtOAc and water. The aqueous phase was extracted with EtOAc (×2) and thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.Further drying under vacuum gave 398 (90 mg, 36%). LCMS: R_(T)=10.71min, [M+H]⁺=440. ¹H NMR δ (ppm) (CDCl₃): 8.37 (1H, s), 7.90 (1H, s),7.20-7.12 (1H, m), 7.06 (1H, dd, J=8.28, 5.28 Hz), 5.85-5.76 (1H, m),4.64-4.30 (4H, m), 4.25-4.10 (3H, m), 3.98-3.87 (1H, m), 3.45-3.35 (2H,m), 1.62 (6H, d, J=6.65 Hz), 1.33 (3H, dd, J=11.04, 6.67 Hz). 1Exchangeable not observed

Example 3992-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(6-pyrrolidin-1-yl-pyridin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene399

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinewere reacted to give 399 (0.078 g, 62%). ¹H NMR (400 MHz, DMSO) δ 8.57(d, J=2.4, 1H), 8.41 (d, J=2.2, 1H), 8.08 (d, J=24.7, 1H), 7.78 (dd,J=8.7, 2.6, 1H), 7.52 (dd, J=8.4, 2.5, 1H), 7.13 (d, J=8.4, 1H), 6.57(d, J=8.7, 1H), 5.79 (dt, J=13.1, 6.5, 1H), 4.35 (dd, J=39.9, 34.8, 2H),3.65-3.37 (m, 6H), 2.11-1.80 (m, 4H), 1.58 (d, J=6.6, 6H). MS (ESI(+)):m/z 459.2 (M+H)

Example 4001-Isopropyl-5-{8-[1-(3-methyl-oxetan-3-ylmethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H-[1,2,4]triazol-3-ylamine400

Similar to as described in General Procedure C,5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylaminewas reacted with1-((3-methyloxetan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.Purification of the crude reaction mixture by reverse phase HPLC gave400. LCMS: 478.2

Example 4018-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-isopropyl-amide 401

Following Example 267,8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(2-hydroxyethyl)-isopropylamide and2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olwere reacted to give 401. MS: (ESI+)=471.2

Example 4029-(2-Fluoro-5-methyl-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene402

Following the procedure for Example 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6, and 2-fluoro-5-methylpyridin-3-ylboronic acid werereacted to give 402 (0.054 g, 37%). ¹H NMR (400 MHz, DMSO) δ 8.74 (t,J=2.0, 1H), 8.11 (s, 1H), 8.07-7.97 (m, 2H), 7.60 (d, J=8.5, 1H), 7.21(d, J=8.4, 1H), 5.82 (dt, J=13.2, 6.6, 1H), 4.44 (t, J=4.9, 2H), 3.49(t, J=4.9, 2H), 2.37 (s, 3H), 1.54 (d, J=6.6, 6H). MS (ESI(+)): m/z422.1 (M+H)

Example 4032-{4-[2-(5-Amino-2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol403

Similar to as described in General Procedure C,5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylaminewas reacted with1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranylether was accomplished by adding 2N HCl to the crude reaction mixture.Purification by reverse phase HPLC gave 403 as a colorless solid (16mg). LCMS: 438.1

Example 4041-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-3-methoxy-propan-2-ol404

Similar to as described in General Procedure C,8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with1-methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol.Purification of the crude reaction mixture by reverse phase HPLC gave404. LCMS: 481.2.

Example 4052-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-N-methyl-acetamide405

Following the procedure for 355,2-[2-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-imidazol-1-yl]-N-methyl-acetamideand2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olwere reacted under Suzuki palladium conditions to give 405 MS:(ESI+)=497.2. ¹H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 8.15 (s,1H), 7.93 (s, OH), 7.38 (d, J=0.8 Hz, 1H), 7.32 (dd, J=8.3, 1.8 Hz, 1H),7.25 (d, J=1.7 Hz, 1H), 7.05 (d, J=0.8 Hz, 0H), 5.23 (s, 1H), 4.72 (s,1H), 4.34 (t, J=5.0 Hz, 1H), 4.04 (s, 1H), 2.66 (t, J=4.4 Hz, 2H), 1.08(s, 6H)

Example 4068-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene406

Similarly to as described in General Procedure C,8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate.Removal of the tertbutoxycarbonyl protecting group was accomplished withtrifluoroacetic acid in dichloromethane. Purification of the crudereaction mixture by reverse phase HPLC gave 406. LCMS: 448.2

Example 4072-(5-Amino-2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylicacid (1-methyl-azetidin-3-yl)-amide 407

Similar to as described in General Procedure F,5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylaminewas reacted with 1-methyl-3-aminoazetidine hydrochloride to give 407after purification by reverse phase HPLC (15 mg). LCMS: 440.1

Example 4082-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methyl-1H-imidazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene408

Following General Procedure G: Stille coupling to aryl bromides, asolution of8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 in 3 mL of acetonitrile was degassed and treated with 150 mg of1-methyl-4-(tributylstannyl)-1H-imidazole.Tetrakis(triphenylphosphine)palladium(0) (12 mg) was added and thereaction mixture was heated in a microwave reactor at 140° C. for 25min. Concentration and purification by reverse phase HPLC gave 408 as acolorless solid (23 mg, 44%). LCMS: 393.1. ¹H NMR (400 MHz, DMSO) δ 8.32(d, J=8.3 Hz, 1H), 8.10 (s, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.57 (dd,J=8.3, 1.7 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 5.84 (dt, J=13.2, 6.6 Hz,1H), 4.39 (t, J=5.0 Hz, 2H), 3.70 (s, 3H), 3.44 (t, J=5.0 Hz, 2H), 1.56(d, J=6.6 Hz, 6H).

Example 4098-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (2-hydroxy-ethyl)-(tetrahydro-pyran-4-yl)-amide 409

Following the procedures of Example 382, to a well stirred solution of8-[2-methyl-1-(1H-pyrazol-1-yl)propan-2-ol)]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid in DMF at room temperature was added2-(tetrahydro-2H-pyran-4-ylamino)ethanol, followed by the addition ofDIPEA and HATU to give 409. MS: (ESI+)=513.2

Example 4108-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (1-acetyl-piperidin-4-yl)-(2-hydroxy-ethyl)-amide 410

Following the procedures of Example 382, to a well stirred solution of8-[2-methyl-1-(1H-pyrazol-1-yl)propan-2-ol)]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid in DMF at room temperature was added1-(4-(2-hydroxyethylamino)piperidin-1-yl)ethanol, followed by theaddition of DIPEA and HATU to give 410. MS: (ESI+)=554.2

Example 4111-{4-[2-(1-azetidin-3-yl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol411

Following the procedure for 355,2-(1-Azetidin-3-yl-1H-imidazol-2-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olwere reacted under Suzuki palladium conditions to give 411. MS:(ESI+)=463.2. ¹H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.2 Hz, 1H), 8.15 (s,1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.45 (dd, J=8.3, 1.7 Hz, 1H), 7.28 (d,J=1.7 Hz, 1H), 7.14 (s, 1H), 6.16-6.06 (m, 1H), 4.72 (s, 1H), 4.36 (t,J=5.0 Hz, 2H), 4.04 (s, 2H), 3.98 (t, J=8.2 Hz, 2H), 3.82-3.76 (m, 2H),1.10 (s, 6H)

Example 4122-methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propylamine412

To a solution of2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-isobutyramide(0.182 g, 0.000361 mol) in tetrahydrofuran (5.864 mL, 0.07229 mol) underN₂ at 0° C. was added lithium tetrahydroaluminate (1M in THF, 1.44 mL,0.00145 mol) dropwise. The reaction was stirred at room temperature for6 h. The reaction was quenched with saturated Na₂SO₄ until no morehydrogen evolution was observed. MgSO₄ was added and the solution wasfiltered and rinsed with copious amounts of methylene chloride. Themixture was concentrated and purified by reverse-phase HPLC to give 412(12.8 mg) as a colorless solid. MS(ESI+) 490.1. ¹H NMR (400 MHz, DMSO) δ8.36 (s, 1H), 8.29 (s, 1H), 8.26 (d, J=8.3, 1H), 7.98 (s, 1H), 7.49 (dd,J=8.3, 1.7, 1H), 7.37 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.39 (t,J=5.0, 2H), 3.47 (t, J=5.0, 2H), 2.86 (s, 2H), 1.50 (s, 6H)

Example 4132-hydroxy-1-[3-(2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidin-1-yl]-propan-1-one413

Compound 411 (0.110 g, 0.000238 mol) dissolved in N,N-Dimethylformamide(3.72 mL, 0.0480 mol) and treated sequentially withN,N-Diisopropylethylamine (0.248 mL, 0.00143 mol) Acetic acid (0.0270mL, 0.000476 mol) thenN,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (0.108 g, 0.000285 mol). Stir at r.t. overnight. Addsat. sodium bicarbonate, extract with ethyl acetate. Dried combinedorganics over sodium sulfate and concentrated. The crude product waspurified by rHPLC to give 413. MS: (ESI+)=535.2. ¹H NMR (400 MHz, DMSO)δ 8.37 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=5.7 Hz,1H), 7.42 (dd, J=8.2, 1.7 Hz, 1H), 7.28 (d, J=1.7 Hz, 1H), 7.18 (d,J=1.0 Hz, 1H), 6.17 (s, 1H), 5.15 (s, 1H), 4.91 (dd, J=17.5, 8.2 Hz,1H), 4.71 (s, 1H), 4.51 (dd, J=16.3, 10.1 Hz, 2H), 4.36 (t, J=5.6 Hz,2H), 4.20 (d, J=6.5 Hz, 2H), 3.39 (t, J=5.1 Hz, 2H), 1.23 (d, J=6.7 Hz,3H), 1.09 (s, 6H)

Example 4142-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethylamine414

Methanesulfonyl chloride (0.055 mL, 0.74 mmol) was added to a solutionof2-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol(201 mg, 0.48 mmol) in cold dichloromethane (3 mL). After 15 min,saturated sodium bicarbonate was added and the mixture extracted withEtOAc. The combined organics were concentrated and the residue dissolvedin 2 mL of DMSO. Sodium azide (62 mg) was added and the mixture heatedat 70° C. overnight. Aqueous extraction with EtOAc gave the crude azide.The azide was dissolved in THF and water (3 mL, 0.5 mL) and the reactionmixture treated with triphenylphosphine (250 mg, 0.95 mmol). After 8 hat 50° C., the reaction mixture was concentrated and the residuepurified by reverse phase HPLC to give 414 as a colorless solid (160 mg,80%). LCMS: 422.1

Example 4153-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-5-methyl-1H-pyridin-2-one415

Following the procedure for Example 330,9-(2-Fluoro-5-methyl-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene402 was treated with aqueous HCl in DME to give 415 (0.038 g, 93%). ¹HNMR (400 MHz, DMSO) δ 11.58 (s, 1H), 8.94 (d, J=2.3, 1H), 8.10 (s, 1H),7.75 (dd, J=8.4, 2.3, 1H), 7.58 (d, J=2.5, 1H), 7.17 (s, 1H), 7.10 (s,1H), 7.07 (d, J=8.5, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.40 (t, J=4.9,2H), 3.46 (t, J=4.9, 2H), 2.09 (s, 3H), 1.56 (d, J=6.6, 6H). MS(ESI(+)): m/z 420.1 (M+H)

Example 4161-[3-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidin-1-yl]-ethanone416

Compound 411 (0.110 g, 0.000238 mol) dissolved in N,N-Dimethylformamide(3.72 mL, 0.0480 mol) and treated sequentially withN,N-Diisopropylethylamine (0.248 mL, 0.00143 mol) Acetic acid (0.0270mL, 0.000476 mol) thenN,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumHexafluorophosphate (0.108 g, 0.000285 mol). Stir at r.t. overnight. Addsat. sodium bicarbonate, extract with ethyl acetate. Dried combinedorganics over sodium sulfate and concentrated. The crude product waspurified by rHPLC to give 416. MS: (ESI+)=505.2. ¹H NMR (400 MHz, DMSO)δ 8.37 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.95-7.90 (m, 2H), 7.43 (dd,J=8.3, 1.8 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.17 (d, J=1.1 Hz, 1H),6.24-6.13 (m, 1H), 4.78-4.66 (m, 2H), 4.51-4.39 (m, 2H), 4.36 (t, J=5.5Hz, 2H), 4.04 (s, 2H), 3.39 (t, J=5.1 Hz, 2H), 1.84 (s, 3H), 1.10 (s,6H).

Example 4172-Methyl-1-{4-[2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-propan-2-ol417

Following the procedure for 114,8-Bromo-2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 417. MS(ESI+) 500.1. ¹H NMR (400 MHz, CDCl₃) δ 8.56-8.52 (d,J=4.2, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.03 (d, J=8.3, 1H), 7.92 (s,1H), 7.78 (td, J=7.7, 1.8, 1H), 7.32-7.26 (m, 2H), 7.24 (d, J=1.7, 1H),7.16 (d, J=7.9, 1H), 6.17 (s, 2H), 4.71 (s, 1H), 4.34 (t, J=5.0, 2H),4.03 (s, 2H), 3.41 (t, J=5.0, 2H), 1.09 (s, 6H)

Example 418{5-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-1-methyl-1H-imidazol-2-yl}-methanol418

Following the procedure for 114,(5-Bromo-1-methyl-1H-imidazol-2-yl)-methanol was reacted with2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azuleneto give 418. MS(ESI+) 423.1. ¹H NMR (400 MHz, DMSO) δ 8.43 (d, J=8.3,1H), 8.11 (s, 1H), 7.33 (dd, J=8.3, 1.8, 1H), 7.17 (d, J=1.8, 1H), 7.05(s, 1H), 5.92-5.78 (m, 1H), 5.32 (t, J=5.3, 1H), 4.55 (d, J=5.0, 2H),4.42 (t, J=5.0, 2H), 3.72 (s, 3H), 3.47 (t, J=5.0, 2H), 1.56 (d, J=6.6,6H)

Example 4195-(8-azetidin-3-yl-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole419

5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-(2,4-difluorophenyl)-1H-1,2,4-triazole(300 mg, 0.6 mmol) was dissolved in N,N-dimethyacetamide and purged withnitrogen. Added[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (30 mg, 0.04 mmol) and copper(I)iodide (10 mg,0.08 mmol). Bubbled in nitrogen for 10 minutes. Added(1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (230 mg, 0.65mmol) in 2.3 mL DMA. Heated at 80° C. overnight. Complete reaction wasconfirmed by LCMS. Diluted reaction mixture with 1 M HCl and extractedthe t-Boc protected intermediate, tert-butyl3-(2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate,with ethyl acetate. Dried over magnesium sulfate and concentrated invacuo. Purified by flash chromatography (0 to 50% ethyl acetate inhexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours.Complete deprotection was confirmed by LCMS. Concentrated in vacuopurified by HPLC to give 419 (21.1 mg, 7% yield, M=1 437.1).

Example 4202-Methyl-1-{4-[2-(1-oxetan-3-yl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-propan-2-ol420

Following the procedure for 355,8-Bromo-2-(1-oxetan-3-yl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olwere reacted under Suzuki palladium conditions to give 420. MS:(ESI+)=464.1. ¹H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.3 Hz, 1H), 8.15 (s,1H), 7.94 (d, J=1.4 Hz, 2H), 7.47 (dd, J=8.3, 1.7 Hz, 1H), 7.28 (d,J=1.7 Hz, 1H), 7.19 (d, J=1.0 Hz, 1H), 6.38 (p, J=6.8 Hz, 1H), 5.10 (t,J=7.3 Hz, 2H), 4.86 (t, J=6.6 Hz, 2H), 4.72 (s, 1H), 4.36 (t, J=5.0 Hz,2H), 4.04 (s, 2H), 3.38 (t, J=5.0 Hz, 2H), 1.10 (s, 6H)

Example 4211-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propan-2-ol421

To a mixture of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (250 mg, 0.52 mmol) in MeOH (3 mL) was addeddiisopropylethylamine (110 μL, 0.62 mmol) followed by1,2-epoxy-2-methylpropane (230 μL, 2.6 mmol) and the reaction mixturewas stirred at RT for 18 hours. The reaction mixture was concentrated invacuo and the residue purified by flash chromatography (SiO₂, 0-7.5%MeOH in DCM) to give a solid that was recrystallised from heptane togive 421 (87 mg, 38%). LCMS: R_(T)=7.41 min, [M+H]⁺=440. ¹H NMR δ (ppm)(DMSO-d6): 8.26 (1H, d, J=8.17 Hz), 8.06 (1H, d, J=0.59 Hz), 7.16 (1H,dd, J=8.23, 1.81 Hz), 7.00 (1H, d, J=1.76 Hz), 5.83-5.75 (1H, m), 4.32(2H, t, J=5.03 Hz), 4.00 (1H, s), 3.65 (2H, t, J=6.98 Hz), 3.61-3.51(1H, m), 3.39 (2H, t, J=5.08 Hz), 3.14 (2H, t, J=6.52 Hz), 2.32 (2H, s),1.51 (6H, d, J=6.59 Hz), 1.03 (6H, s)

Example 4222-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2,2,2-trifluoro-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene422

Following the procedure of 319,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235, trifluoroethyl triflate and triethylamine were reacted togive 422 isolated as a white solid (105 mg, 52%). LCMS: R_(T)=12.34 min,[M+H]⁺=450. ¹H NMR δ (ppm) (CDCl₃): 8.32 (1H, d, J=8.18 Hz), 7.90 (1H,s), 7.10 (1H, dd, J=8.21, 1.86 Hz), 6.98 (1H, d, J=1.83 Hz), 5.93-5.84(1H, m), 4.39 (2H, t, J=5.05 Hz), 3.90 (2H, t, J=7.29 Hz), 3.82-3.73(1H, m), 3.42-3.33 (4H, m), 3.04 (2H, q, J=9.39 Hz), 1.61 (6H, d, J=6.63Hz)

Example 4238-(1-Isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene423

A suspension of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (215 mg, 0.45 mmol) in dry DCE (4.5 mL) under argon wastreated with acetone (49 μL, 0.67 mmol) followed by sodiumtriacetoxyborohydride (190 mg, 0.89 mmol). The reaction mixture wasstirred at RT for 18 hours. Aqueous saturated sodium bicarbonatesolution and DCM were added and the phases were separated. The aqueousphase was extracted with DCM (×2) and the combined organic phase waswashed with water followed by brine, dried (Na₂SO₄) and concentrated invacuo. The resultant solid was triturated with ether, to give 423 as anoff-white solid (115 mg, 63%). LCMS: R_(T)=7.44 min, [M+H]⁺=410. ¹H NMRδ (ppm) (CDCl₃): 8.30 (1H, d, J=8.17 Hz), 7.89 (1H, s), 7.07 (1H, dd,J=8.20, 1.83 Hz), 6.96 (1H, d, J=1.81 Hz), 5.93-5.84 (1H, m), 4.38 (2H,t, J=5.05 Hz), 3.79 (2H, t, J=7.00 Hz), 3.74-3.63 (1H, m), 3.39 (2H, t,J=5.06 Hz), 3.12 (2H, m), 2.38 (1H, m), 1.60 (6H, d, J=6.63 Hz), 0.97(6H, d, J=6.21 Hz)

Example 424(S)-3-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propane-1,2-diol424

Following the procedure for 322,8-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with acid, warming the reaction at 50° C. overnight. Thecrude product was triturated with diethyl ether to give 424 (72 mg,60%). LCMS: R_(T)=7.02 min, [M+H]⁺=442. ¹H NMR δ (ppm) (DMSO-d6): 10.50(1H, s), 8.31 (1H, dd, J=8.22, 5.90 Hz), 8.07 (1H, s), 7.30-7.22 (1H,m), 7.17 (1H, dd, J=15.00, 1.80 Hz), 5.81-5.72 (1H, m), 4.42-4.22 (5H,m), 4.22-4.10 (1H, m), 3.76 (1H, d, J=9.24 Hz), 3.47-3.22 (5H, m),3.20-3.09 (1H, m), 1.51 (6H, d, J=6.59 Hz). 1 Proton obscured by waterpeak. 2 Exchangeable protons not observed

Example 425(1-Amino-cyclopropyl)-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-methanone425

To a suspension of(1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamicacid tert-butyl ester (225 mg, 0.41 mmol) in MeOH (3.1 mL) was added 4NHCl/dioxan (1.0 mL, 4.1 mmol) and the reaction mixture was stirred for18 hours. The resulting solid was filtered off and washed with diethylether before being partitioned between DCM and an aqueous saturatedsodium bicarbonate solution. The phases were separated and the aqueousphase was extracted with DCM (×2). The combined organic extracts werewashed with brine, dried (Na₂SO₄) and concentrated in vacuo. Theresultant residue was purified by flash chromatography (SiO₂, 0-8% 2NNH₃/MeOH in DCM). The resulting solid was suspended in ether andcollected by filtration to give 425 as a white solid (108 mg, 59%).LCMS: R_(T)=7.96 min, [M+H]⁺=451. ¹H NMR δ (ppm) (DMSO-d6): 8.35 (1H, d,J=8.20 Hz), 8.02 (1H, s), 7.20 (1H, dd, J=8.22, 1.81 Hz), 7.05 (1H, s),5.86-5.78 (1H, m), 4.59 (2H, t, J=9.01 Hz), 4.40 (2H, t, J=5.07 Hz),4.20 (2H, d, J=7.67 Hz), 3.85 (1H, t, J=7.50 Hz), 3.44 (2H, t, J=5.08Hz), 2.18 (2H, s), 1.58 (6H, d, J=6.59 Hz), 1.09-1.06 (2H, m), 0.70 (2H,q, J=3.28 Hz)

Example 4264-{8-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-5-isopropyl-2-methyl-2,4-dihydro-[1,2,4]triazol-3-one426

Following the procedure for 322,5-isopropyl-2-methyl-4-(8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,4-dihydro-[1,2,4]triazol-3-onewas reacted with acid. The product was precipitated from the reactionmixture by the addition of ether and collected by filtration to give 426as a white solid (8.5 mg, quant.). LCMS: R_(T)=11.47 min, [M+H]⁺=453. ¹HNMR δ (ppm) (DMSO-d6): 8.16 (1H, s), 8.10 (1H, d, J=8.26 Hz), 7.89 (1H,s), 7.36 (1H, dd, J=8.26, 1.84 Hz), 7.23 (1H, d, J=1.81 Hz), 4.32 (2H,t, J=5.01 Hz), 4.11 (2H, t, J=5.65 Hz), 3.90-3.82 (1H, m), 3.72 (2H, t,J=5.66 Hz), 3.38 (3H, s), 1.31 (6H, d, J=6.81 Hz). 2 Protons obscured bywater peak. 1 Exchangeable proton not seen.

Example 4272-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propan-1-ol427

A solution of2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionicacid methyl ester (147 mg, 0.31 mmol) in anhydrous THF (5 mL) at 0° C.under nitrogen was treated dropwise with a 1M solution of LiAlH₄ in THF(0.47 mL, 0.47 mmol) and the mixture was stirred for 15 minutes thenallowed to warm to RT. After 1.5 hours the mixture was cooled to 0° C.and quenched by cautious addition of water. EtOAc was added and theorganic layer was washed with brine, dried (Na₂SO₄) and concentrated invacuo. The resultant residue was dissolved in DCM (20 mL) and treatedwith 4N HCl/dioxan (1 mL). The resulting solid was filtered off, washedwith ether and dried to give 427 (142 mg, quant.). LCMS: R_(T)=7.54 min,[M+H]⁺=440. ¹H NMR δ (ppm) (DMSO-d6): 10.61 (1H, s), 8.32 (1H, d, J=8.21Hz), 8.07 (1H, s), 7.22-7.16 (1H, m), 7.06 (1H, d, J=1.80 Hz), 5.81-5.72(1H, m), 4.55 (1H, td, J=10.55, 4.79 Hz), 4.38-4.26 (3H, m), 4.16-3.92(3H, m), 3.46-3.37 (5H, m), 1.53-1.48 (6H, m), 1.27-1.14 (6H, m)

Example 4282-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamino}-2-methyl-propan-1-ol428

2-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-olfrom Example 356, was coupled with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olunder Suzuki conditions to give 428. Yield 18%. MS(ESI+): 429.2. 1H NMR(400 MHz, DMSO) δ 8.14-8.04 (m, 2H), 7.87 (s, 1H), 7.29 (dd, J=8.2, 1.8,1H), 7.17 (d, J=1.8, 1H), 7.07 (s, 1H), 4.97 (t, J=5.6, 1H), 4.70 (s,1H), 4.26 (t, J=5.0, 2H), 4.02 (s, 2H), 3.58 (d, J=5.6, 2H), 3.05 (t,J=5.0, 2H), 1.34 (s, 6H), 1.09 (s, 6H)

Example 4291-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-5,5-dimethyl-imidazolidin-2-one429 Step 1: 1-(2-Methyl-1-(tritylamino)propan-2-yl)thiourea

2-Methyl-N1-tritylpropane-1,2-diamine, prepared from2-methylpropane-1,2-diamine and trityl chloride (EP1204654) in yield of44%, was coupled with benzoylisothiocyanate to giveN-(2-methyl-1-(tritylamino)propan-2-ylcarbamothioyl)benzamide(US2008/45579) which was then reacted with lithium hydroxide to give1-(2-methyl-1-(tritylamino)propan-2-yl)thiourea. Yield 79%. 1H NMR (400MHz, CDCl3) δ 7.40-7.12 (m, 16H), 6.30 (s, 1H), 2.38 (d, J=8.3, 2H),2.15 (t, J=8.3, 1H), 1.31 (s, 6H)

Step 2:N2-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-2-methylpropane-1,2-diaminehydrobromide

Following the Example 356,1-(2-methyl-1-(tritylamino)propan-2-yl)thiourea was reacted with4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in ethanol under refluxfor 18 hours to giveN2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-2-methylpropane-1,2-diaminehydrobromide. Yield 68%. MS(ESI+): 368.0

Step 3:1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one

Following the Example 356,N2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-2-methylpropane-1,2-diaminehydrobromide was reacted with triphosgene in tetrahydrofuran andpurified on silicagel column eluting with 50% of ethyl acetate inheptane to give1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one.Yield 51%. MS(ESI+): 393.9

Step 4

1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-onewas coupled with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olunder Suzuki conditions to give 429. Yield 12%. MS(ESI+): 454.1. 1H NMR(400 MHz, DMSO) δ 8.18 (d, J=8.2, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.61(s, 1H), 7.35 (dd, J=8.2, 1.8, 1H), 7.21 (d, J=1.7, 1H), 4.71 (s, 1H),4.31 (t, J=5.0, 2H), 4.03 (d, J=5.6, 2H), 3.18 (dd, J=9.3, 5.1, 3H),1.72 (s, 6H), 1.09 (s, 6H)

Example 4302-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonylmethyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene430

Following the procedure for 114,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 was reacted with1-Methanesulfonylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazoleto give 430. MS(ESI+) 471.1. ¹H NMR (400 MHz, DMSO) δ 8.36 (m, 2H), 8.19(s, 1H), 8.10 (s, 1H), 7.49 (dd, J=8.3, 1.8, 1H), 7.36 (d, J=1.7, 1H),5.84 (m, 1H), 5.75 (s, 2H), 4.40 (t, J=5.0, 2H), 3.46 (t, J=5.0, 2H),3.06 (s, 3H), 1.56 (d, J=6.6, 6H)

Example 431N2-(2-chloro-5-(2-hydroxyethylcarbamoyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide431

To a mixture of3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and 2-aminoethanol (0.56g, 9.13 mmol) by sequence under nitrogen atmosphere at room temperature.The reaction mixture was stirred overnight, diluted with water. Theresulting precipitate was washed with water and EtOAc to give8-bromo-N-(2-chloro-5-(2-hydroxyethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(2.52 g, yield 77%). LC-MS: (ESI, m/z)=535 [M+H]⁺

8-Bromo-N-(2-chloro-5-(2-hydroxyethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(0.5 g, 0.933 mmol) was dissolved in 5 mL of pyridine. The mixture wasstirred at 0° C. and acetic anhydride (0.2 g, 2 eq) was added dropwise.It was stirred at room temperature for overnight. The mixture was pouredinto ice water and the mixture was extracted by DCM. The combinedorganics were dried and evaporated in vacuum to afford the acetylatedproduct,2-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzamido)ethylacetate (0.45 g, yield: 83%). LC-MS: (ESI, m/z)=577 [M+H]⁺

A suspension of2-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzamido)ethylacetate (400 mg, 0.69 mmol), Pd(OAc)₂ (10 mg, 0.045 mmol), Xantphos (40mg, 0.069 mmol), MeNH₂.HCl (70 mg, 1.04 mmol) and Na₂CO₃ (219 mg, 2.07mmol) in toluene (5 mL) was heated at 80° C. under atmosphere of CO fromballoon overnight. Then it was filtrated and concentrated, the crudeproduct was dissolved in 10 mL of THF/H₂O=1:1. 0.14 g of NaOH was added.The mixture was stirred at room temperature for overnight. The mixturewas extracted by DCM and purified by column (EtOAc:MeOH=10:1) to afford431 (72.6 mg, yield: 20%)¹H NMR (DMSO-d6, 400 MHz): δ8.62 (t, J=5.6 Hz,1H), 8.41 (d, J=4.8 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.74(d, J=8.4 Hz, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 6.58 (s, 1H), 4.73 (t,J=5.6 Hz, 1H), 4.16 (s, 2H), 3.50 (dd, J=6.0, 10.0 Hz, 2H), 3.31-3.27(m, 5H), 2.94 (s, 2H), 2.72 (d, J=4.4 Hz, 3H). LC-MS: (ESI, m/z)=514[M+H]⁺

Example 432N2-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide432

A suspension of8-bromo-N-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(400 mg, 0.70 mmol), Pd(OAc)₂ (8 mg, 0.035 mmol), Xantphos (41 mg, 0.070mmol), MeSO₂(CH₂)₂NH₂.HCl (169 mg, 1.06 mmol) and Na₂CO₃ (224 mg, 2.11mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. underatmosphere of CO from balloon for 3 h. Then it was filtrated andconcentrated, the crude product was purified by flash columnchromatography on silica gel (petroleum ether:EtOAc=2:1˜1:5 as elutedsolvent) to give a white solid which was washed with DCM and dried togive 432 (121.3 mg, yield: 27%). ¹H NMR (DMSO-d6, 400 MHz): δ 8.73-6.60(m, 8H, NH, ArH), 4.75-3.02 (m, 18H). LC-MS: (ESI, m/z)=638 [M+H]⁺

Example 433{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(1-methyl-azetidin-3-yl)-amine433

3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidine-1-carboxylicacid tert-butyl ester (300 mg, 0.54 mmol) was dissolved in THF (20 mL),and LiAlH₄ was added in the solution. The reaction mixture was stirredat room temperature for 2 hr, filtered to gather the solution, washed byDCM (10 mL), and separated by TLC (DCM/EtOAc=10:1) to give 433 (128.3mg, yield: 51%). ¹H NMR (DMSO-d₆, 400 MHz): δ8.36 (s, 1H), 8.28-7.95 (m,2H), 7.75-7.56 (m, 1H), 7.54 (s, 1H), 6.98-6.83 (m, 1H), 6.73-6.55 (m,1H), 4.10 (m, 6H), 3.55 (s, 1H), 3.48 (s, 1H), 3.02 (t, J=8.0 Hz, 2H).LC-MS (ESI): m/z=467 [M+H]⁺

Example 434{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-oxetan-3-yl-amine434

Compound 134 (200 mg, 0.5 mmol) was dissolved in THF, and oxetan-3-one(252 mg, 0.35 mmol) was added at 0° C. The mixture was warmed to 80° C.and stirred for 0.5 h at this temperature. It was cooled to 0° C.,NaBH(CN)₃ (67 mg, 0.6 mmol) was added. Then the mixture was warmed to80° C. and stirred for further 0.5 h at this temperature. The reactionmixture was filtered to gather the solution. Then water was added intothe solution. It was extracted by DCM (20 mL×3). The combined organicswere dried over Na₂SO₄, concentrated in vacuo, and separated by prep TLC(EtOAc/hexanes=4:1) to give 434 (115 mg, yield: 50%). ¹H NMR (DMSO-d6,400 MHz): δ9.42 (s, 1H), 8.42 (s, 1H), 8.00-7.49 (m, 4H), 7.12 (s, 1H),7.04 (d, J=9.6 Hz, 1H), 4.85-4.83 (m, 1H), 4.58-4.38 (m, 4H), 3.65 (t,J=6.4 Hz, 2H), 2.93 (t, J=6.4 Hz, 2H). LC-MS (ESI): m/z=454 [M+H]⁺

Example 435Azetidin-3-yl-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-amine435

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(812 mg, 2.0 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (412 mg,2.4 mmol), Pd(OAc)2 (45 mg, 0.20 mmol), Xphos (95 mg, 2.0 mmol), t-BuONa(460 mg, 4.0 mmol) and dioxane (4.0 mL) were added into a 10 mL ofsealed tube, and the mixture was heated by microwave at 112° C. for 7min under N₂. The reaction mixture was filtered to gather the solutionand water was added. The mixture was extracted by DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, concentrated in vacuo,and purified by column (DCM/EtOAc=10:1) to give3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidine-1-carboxylicacid tert-butyl ester (703 mg, yield: 64%). ¹HNMR (Acetone-d₆, 400 MHz):δ7.99 (s, 1H), 7.76-7.73 (m, 1H), 7.38-7.27 (m, 2H), 7.14 (s, 1H), 7.00(d, J=8.8 Hz, 1H), 6.37 (d, J=8.8 Hz, 1H), 6.27 (d, J=5.2 Hz, 1H),4.29-4.09 (m, 6H), 3.57 (s, 1H), 3.02 (t, J=4.8 Hz, 2H), 1.34 (s, 9H).ESI-MS: m/z=553 [M+H⁺]

3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidine-1-carboxylicacid tert-butyl ester (558 mg, 1.0 mmol) was dissolved in EtOAc (10 mL).Hydrogen chloride dissolved in Ethyl acetate (EtOAc—HCl, 10 mL) wasadded by drop to the solution and the reaction mixture was stirred atroom temperature for 2 h. The reaction mixture was filtered to gatherthe solid which was washed with DCM (10 mL) to give 435 (0.43 g, yield:87%). ¹HNMR (DMSO-d₆, 400 MHz): δ7.99 (s, 1H), 7.74-7.72 (m, 1H),7.36-7.27 (m, 2H), 7.14 (s, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.38-6.26 (m,2H), 4.11-4.09 (m, 6H), 3.56 (s, 1H), 3.02 (t, J=4.8 Hz, 2H). ESI-MS:m/z=453 [M+H⁺]

Example 4362-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-5-methyl-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene436

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(416 mg, 1.0 mmol) was dissolved in CH₃CN/H₂O (3 mL), Pd(dppf)₂Cl₂ (58mg, 0.10 mmol), Cs₂CO₃ (658 mg, 2.0 mmol) were added in a 10 mL ofsealed tube. The reaction mixture was heated by microwave at 120° C. for20 min under N₂. The reaction mixture was concentrated in vacuo. Theresidue was dissolved in DCM (20 mL), washed by water, dried by Na₂SO₄,concentrated in vacuo, and separated by prep. TLC (EtOAc/Hexanes=1:3) togive 436 (300 mg, yield: 61%). ¹HNMR (DMSO-d6, 400 MHz): δ8.68 (s, 1H),8.43-8.34 (m, 1H), 8.12-8.01 (m, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.84-7.78(m, 1H), 7.58-7.50 (m, 1H), 7.26 (s, 1H), 4.39 (m, 2H), 3.39 (s, 2H),3.00 (s, 2H), 2.41 (s, 3H). LC-MS (ESI): m/z=492 [M+H]¹

Example 4372-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-[5-methyl-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene437

Compound 436 (200 mg, 0.41 mmol) was dissolved in NMP (2 mL),N-Methyl-piperazine (82 mg, 0.82 mmol) was added in it. The reactionmixture was heated by mw at 150° C. for 90 min. The reaction mixture wasconcentrated in vacuo, dissolved in DCM (20 mL). And the organic layerwas washed by water, dried by Na₂SO₄, concentrated in vacuo, andseparated by prep. TLC (EtOAc/Hexanes=1:3) to give 437 (72.1 mg, yield:31%). ¹H NMR (DMSO-d₆, 400 MHz): δ9.759 (s, 1H), 8.58 (s, 1H), 8.47 (t,J=11.8 Hz, 1H), 8.25 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.63-7.53 (m, 2H),7.29-7.19 (m, 2H), 7.08 (d, J=11.2 Hz, 2H), 4.36 (t, J=4.8 Hz, 2H),4.20-4.11 (m, 2H), 3.74-3.68 (m, 2H), 3.29 (s, 6H), 2.76 (s, 3H), 2.32(s, 3H). LC-MS (ESI): m/z=572 [M+H]⁺

Example 438N2-(2-chloro-5-((S)-2-hydroxypropylcarbamoyl)phenyl)-N2-methyl-N8-(2-(methylsulfonyl)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide438

A suspension of8-bromo-N-(2-chloro-5-((S)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(400 mg, 0.73 mmol), Pd(OAc)₂ (8 mg, 0.037 mmol), Xantphos (42 mg, 0.073mmol), MeSO₂(CH₂)₂NH₂.HCl (175 mg, 1.095 mmol) and Na₂CO₃ (232 mg, 2.19mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. underatmosphere of CO from balloon overnight. Then it was filtrated andconcentrated, the crude product was purified by pre-TLC (eluted byDCM:MeOH=10:1) to give 438 (191.9 mg, yield 42%). ¹H NMR (DMSO-d6, 400MHz): δ8.74 (t, J=5.2 Hz, 1H, NH), 8.62 (t, J=5.2 Hz, 1H, NH), 8.12-7.44(m, 6H, ArH), 6.61 (s, 1H, ═CH), 4.77 (d, J=4.8 Hz, 1H, OH), 4.20 (br s,2H, CH₂), 3.80-3.75 (m, 1H, CH), 3.67-2.98 (m, 14H, CH₃, CH₂), 1.05 (t,J=6.0 Hz, 3H, CH₃). LC-MS: (ESI, m/z)=620 [M+H]⁺

Example 4392-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-isobutyramide439

Following the procedure for 240,2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionicacid was reacted with ammonium chloride to give 439. MS(ESI+) 464.1. ¹HNMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H),8.02 (s, 1H), 7.50 (dd, J=8.3, 1.8, 1H), 7.39 (d, J=1.7, 1H), 7.17 (br,1H), 6.79 (br, 1H), 5.93-5.74 (m, 1H), 4.39 (t, J=5.0, 2H), 3.45 (t,J=5.0, 2H), 1.75 (s, 6H), 1.56 (d, J=6.6, 6H)

Example 4402-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-imidazol-1-yl}-ethanol440

Similar to described in General Procedure G:8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with a mixture of1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazoleand1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazoleto give 440 after THP-removal with aqueous HCl purification by reversephase HPLC (55 mg). LCMS: 437.1.

Example 4412-{5-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-imidazol-1-yl}-ethanol441

Similar to described in General Procedure G:8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with a mixture of1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazoleand1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazoleto give 441 after THP-removal with aqueous HCl purification by reversephase HPLC (4.8 mg). LCMS: 437.1.

Example 4421-(4-{2-[2-(2-Hydroxy-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-2-methyl-propan-2-ol442

Following the procedure for 114,2-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-ethanolwas reacted with2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 442. MS(ESI+) 453.1. ¹H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3,1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.42 (dd, J=8.3, 1.8,1H), 7.30 (d, J=1.7, 1H), 4.94 (t, J=5.5, 1H), 4.89 (t, J=5.9, 2H), 4.71(s, 1H), 4.39 (t, J=5.0, 2H), 4.04 (s, 2H), 3.91 (q, J=5.8, 2H), 3.44(t, J=5.0, 2H), 1.10 (s, 6H)

Example 4432-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanesulfonicacid dimethylamide 443

Following the procedure for 320,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 and ethenesulfonic acid dimethylamide were reacted. Thereaction mixture was concentrated in vacuo and the residue partitionedbetween DCM and water. The organic phase was washed with water followedby brine, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by flash chromatography (SiO₂, 2% MeOH in DCM) to give 443 as abeige solid (117 mg, 75%). LCMS: R_(T)=7.69 min, [M+H]⁺=503. ¹H NMR δ(ppm) (CDCl₃): 8.31 (1H, d, J=8.17 Hz), 7.89 (1H, s), 7.08 (1H, dd,J=8.21, 1.86 Hz), 6.99-6.96 (1H, m), 5.92-5.83 (1H, m), 4.38 (2H, t,J=5.05 Hz), 3.77 (2H, t, J=6.90 Hz), 3.74-3.64 (1H, m), 3.39 (2H, t,J=5.06 Hz), 3.23 (2H, t, J=6.67 Hz), 3.00-2.92 (4H, m), 2.87 (6H, s),1.60 (6H, d, J=6.64 Hz)

Example 4442-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propan-1-one444

Following the procedure for 318,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 and 2-hydroxyisobutyric acid were reacted in DMF.Purification by trituration with ether then reverse phase preparativeHPLC (Gemini C₁₈ column, gradient 40-98% MeOH in H₂O+0.1% HCO₂H) gave444 as a white solid (39 mg, 21%). LCMS: R_(T)=11.04 min, [M+H]⁺=454. ¹HNMR δ (ppm) (CDCl₃): 8.36 (1H, d, J=8.19 Hz), 7.90 (1H, s), 7.11 (1H,dd, J=8.22, 1.90 Hz), 7.00-6.96 (1H, m), 5.92-5.83 (1H, m), 4.74 (1H, d,J=9.42 Hz), 4.46 (1H, t, J=9.76 Hz), 4.39 (3H, t, J=5.47 Hz), 4.14 (1H,s), 3.87-3.78 (1H, m), 3.65 (1H, s), 3.40 (2H, t, J=5.00 Hz), 1.60 (6H,d, J=6.63 Hz), 1.43 (6H, s)

Example 4452-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-sulfonyl}-ethanol445

Following the procedure for 394,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235, 2-chloroethanesulfonyl chloride, and 1.0 equivalents oftriethylamine were reacted to give 445. LCMS: R_(T)=8.49 min,[M+H]⁺=476. ¹H NMR δ (ppm) (DMSO-d6): 8.29 (1H, d, J=8.20 Hz), 8.06-8.03(1H, m), 7.22 (1H, dd, J=8.27, 1.86 Hz), 7.13 (1H, d, J=1.82 Hz),5.82-5.72 (1H, m), 4.36-4.26 (4H, m), 4.10-3.94 (3H, m), 3.45-3.35 (4H,m), 2.72-2.65 (2H, m), 1.50 (6H, d, J=6.59 Hz). 1 Exchangeable protonnot seen

Example 4462-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-isobutyramide446

A solution of2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile(0.26 g, 0.6 mmol) in DMSO (5 mL) was treated with potassium carbonate(16 mg, 0.12 mmol) followed by hydrogen peroxide (30% aq., 0.33 mL) andthe mixture was heated at 45° C. for 18 hours then at 50° C. for a fewmore hours. Further hydrogen peroxide (33 mL, 30% aq.) was added and themixture heated at 50° C. for 18 hours. After cooling, water was addedand the mixture was extracted with EtOAc (×5). The combined organicextracts were dried (Na₂SO₄), and concentrated in vacuo and the residuepurified by flash chromatography (SiO₂, first time with 0-10% MeOH inEtOAc then second time with 0-5% MeOH in DCM). Further purification wasby reverse-phase preparative HPLC (Gemini C₁₈ column, gradient 30-40%MeOH in H₂O+0.1% HCO₂H). A solution of the product in a mixture ofchloroform and DCM was treated with 0.2M HCl in ether (0.32 mL) and thenconcentrated in vacuo to give 446 (27 mg, 9%). LCMS: R_(T)=7.41 min,[M+H]⁺=453. ¹H NMR δ (ppm) (DMSO-d6): 10.79 (1H, s), 8.34-8.28 (1H, m),8.06 (1H, s), 7.82 (1H, d, J=17.45 Hz), 7.65 (1H, d, J=4.94 Hz),7.27-7.16 (1H, m), 7.07 (1H, d, J=1.80 Hz), 5.80-5.72 (1H, m), 4.47 (1H,td, J=10.76, 4.67 Hz), 4.37-4.26 (3H, m), 4.20-3.94 (3H, m), 3.41 (2H,q, J=4.96 Hz), 1.55-1.45 (12H, m)

Example 4475-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-one447

Similarly to as described in General Procedure C,5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-onewas reacted with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol.Purification of the crude reaction mixture by reverse phase HPLC gave447. LCMS: 467.1. ¹H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 8.25 (d, J=8.3Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.43 (dd, J=8.3, 1.8 Hz, 1H), 7.29(d, J=1.8 Hz, 1H), 5.35-5.18 (m, 1H), 4.71 (s, 1H), 4.37 (t, J=5.0 Hz,2H), 4.03 (s, 2H), 3.39 (dd, J=17.6, 12.4 Hz, 2H), 1.56 (d, J=6.9 Hz,6H), 1.09 (s, 6H)

Example 448N2-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N2,N8-dimethyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-dicarboxamide448

To a mixture of 3,3-difluoroazetidine hydrochloride (1.18 g, 9.13 mmol),DIPEA (5 mL), HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoicacid (3.00 g, 6.09 mmol) under nitrogen atmosphere at room temperature.The reaction mixture was stirred for 5 h, diluted with water, extractedwith EtOAc. The organic layer was dried over Na₂SO₄, concentrated invacuo to give8-bromo-N-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(3.2 g, yield 93%). ¹H NMR (DMSO, 400 MHz): δ7.56-6.59 (m, 7H, ArH),4.76-4.48 (m, 4H, 2CH₂), 4.31 (t, J=5.2 Hz, 2H, CH₂), 3.33 (s, 3H, CH₃),2.96 (t, J=5.2 Hz, 2H, CH₂)

A suspension of8-bromo-N-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide(400 mg, 0.70 mmol), Pd(OAc)₂ (8 mg, 0.035 mmol), Xantphos (41 mg, 0.070mmol), MeNH₂.HCl (71 mg, 1.06 mmol) and Na₂CO₃ (224 mg, 2.11 mmol) intoluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere ofCO from balloon for 4 h, and then filtered and concentrated. The crudeproduct was purified by pre-HPLC to give 448 (121.4 mg, yield 32%). ¹HNMR (DMSO, 400 MHz): δ8.45 (m, 1H, NH), 7.98-7.44 (m, 6H, ArH), 6.60 (s,1H, ═CH), 4.75 (brs, 2H, CH₂), 4.48 (br s, 2H, CH₂), 4.20 (s, 2H, CH₂),3.30 (s, 3H, CH₃), 2.99 (s, 2H, CH₂), 2.75 (d, J=4.4 Hz, 3H, CH₃).LC-MS: (ESI, m/z)=546 [M+H]⁺

Example 449{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-aceticacid 449

Compound 134 (800 mg, 2.0 mmol) was dissolved in THF (20 mL). It wasstirred at 0° C. and NaH (58 mg, 2.4 mmol) was added. Then the mixturewas warmed to r.t. and stirred for further 0.5 h. The mixture was cooledto 0° C. and tert-butyl 3-bromopropanoate (502 mg, 2.4 mmol) was added.Later, it was warmed to 80° C. for 2 h. The reaction mixture wasfiltered to gather the solution. Then water was added into the solution.It was extracted by DCM (20 mL×3). The combined organics were dried overNa₂SO₄, concentrated in vacuo, and separated by prep TLC (DCM) to give{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-aceticacid tert-butyl ester (900 mg, yield: 90%)¹HNMR (CDCl₃, 400 MHz): δ 8.04(s, 1H), 7.45-7.52 (m, 1H), 7.42 (s, 1H), 7.06-6.93 (m, 4H). 4.25-4.15(m, 2H), 4.08-3.99 (m, 2H), 3.06 (s, 2H), 1.38 (s, 9H). LC-MS (ESI):m/z=512 [M+H]⁺

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-aceticacid tert-butyl ester (900 mg, 1.76 mmol) was dissolved in dioxane-HCl(20 mL), and the reaction mixture was stirred at room temperature for0.5 h. The reaction mixture was filtered to gather the solid. Theresulting solid was washed by DCM (10 mL) to give 449 as HCl salt (500mg, yield: 57%). ¹H NMR (DMSO-d₆, 400 MHz): δ8.27 (s, 1H), 7.82-7.90 (m,1H), 7.63-7.69 (m, 1H), 7.61-7.62 (m, 2H), 7.35-7.40 (m, 2H), 7.21 (s,1H), 6.95 (s, 2H), 6.52 (d, J=8.8 Hz, 1H), 4.15 (t, J=4.0 Hz, 2H), 3.88(s, 2H), 3.05 (t, J=4.8 Hz, 2H). LC-MS (ESI): m/z=456 [M+H]⁺

Example 4503-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-propane-1,2-diol450

3-Aminopropane-1,2-diol (400 mg, 4.4 mmol) was dissolved in EtOAc—HCl(20 mL). And the reaction mixture was stirred at r.t. for 30 min. Thereaction mixture was concentrated in vacuo to get to the white solid.The white solid was added in 2,2-dimethoxy-propane (10 mL) andtoluene-4-sulfonic acid (86 mg, 0.5 mmol) was added into the mixture.The reaction mixture was stirred at 60° C. for 12 h. The reactionmixture was concentrated in vacuo, washed by acetone to give(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (350 mg, yield: 46%). ¹HNMR(DMSO-d6, 400 MHz): δ8.08 (s, 2H), 4.32 (s, 1H), 4.05 (q, J=4.8 Hz, 1H),3.73 (t, J=6.4 Hz, 1H), 3.00-2.78 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H)

9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene(300 mg, 0.72 mmol), C-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-methyl-amine(101 mg, 0.86 mmol), Pd₂(dba)₃ (66 mg, 0.072 mmol), Xphos (34 mg, 0.072mmol), t-BuONa (138 mg, 1.44 mmol) and dioxane (2 mL) was added in a 10mL of sealed tube. The reaction mixture was heated by microwave at 112°C. for 7 min under N₂. The reaction mixture was filtered to gather thesolution. Then water was added in the solution and extracted by DCM(3×50 mL); The combined organic layer was dried by Na₂SO₄, concentratedin vacuo, separated by TLC (DCM) to{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-amine(248 mg, yield: 67%). ¹H NMR (DMSO-d₆, 400 MHz): δ8.16 (s, 1H), 7.79 (q,J=2.8, 8.4 Hz, 1H), 7.76-7.55 (m, 1H, 7.31 (t, J=8.4 Hz, 1H), 6.99 (t,J=4.4 Hz, 1H), 6.52 (t, J=6.0 Hz, 1H, 6.33 (d, J=8.4 Hz, 1H), 4.12-3.81(m, 5H), 3.52-3.49 (m, 2H), 2.96 (t, J=4.8 Hz, 2H), 1.87 (s, 2H), 1.18(d, 6H) LC-MS (ESI): m/z=512 [M+H]⁺

{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-amine(240 mg, 0.52 mmol) was dissolved in dioxane-HCl (20 mL), and then thereaction mixture was stirred at room temperature for 2 h. Then thereaction mixture was filtered to gather the solid. Then the solid waswashed by DCM (10 mL) to give 450 (130 mg, yield: 53%). ¹HNMR (DMSO-d₆,400 MHz): δ8.26 (s, 1H), 7.91-7.85 (m, 1H), 7.70-7.55 (m, 1H), 7.42-7.37(m, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.99 (s, 1H), 4.15 (t, J=4.4 Hz, 2H),3.67-3.03 (m, 8H) LC-MS (ESI): m/z=472 [M+H]⁺

Example 4512-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-N,N-dimethyl-acetamide451

Compound 448 (150 mg, 0.33 mmol) was dissolved in THF (20 mL), DIPEA (85mg, 0.66 mmol), HATU (250 mg, 0.66 mmol), dimethyl-amine (83 mg, 0.66mmol) was added in it. The reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was concentrated in vacuo,dissolved in DCM (10 mL). The organic layer was washed by water, driedby Na₂SO₄, concentrated in vacuo, separated by TLC to give 451 (21 mg,yield: 13%). ¹HNMR (DMSO-d6, 400 MHz): δ 9.46 (s, 1H), 8.35-8.31 (m,1H), 7.98-7.94 (m, 1H), 7.90-7.74 (m, 1H), 7.49-7.44 (m, 1H), 7.29 (s,1H), 7.18 (s, 2H), 7.14-7.00 (m, 1H), 6.63 (d, J=8.8 Hz, 2H), 4.22 (s,2H), 4.07 (s, 2H), 3.02 (m, 2H). LC-MS (ESI): m/z=483 [M+H]⁺

Example 4522-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-acetamide452

Compound 448 (150 mg, 0.33 mmol) was dissolved in THF (10 mL), and DIPEA(85 mg, 0.66 mmol), HATU (250 mg, 0.66 mmol), (NH₄)₂CO₃ (64 mg, 0.66mmol) were added. The reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated in vacuo, and dissolvedin DCM (30 mL). The mixture was washed by water, dried over Na₂SO₄,concentrated in vacuo, and separated by prep. TLC (EtOAc/MeOH=10:1) togive 452 (15 mg, yield: 10%). ¹H NMR (DMSO-d₆, 400 MHz): δ8.34 (s, 1H),7.97-7.91 (m, 1H), 7.82-7.73 (m, 1H), 7.49-7.32 (m, 1H), 7.28-7.21 (m,1H), 7.05 (s, 1H), 7.03 (s, 1H), 6.86 (s, 1H), 6.59 (d, J=8.8 Hz, 1H),4.21 (m, 2H), 4.16 (m, 2H), 3.10 (t, J=4.4 Hz, 2H). LC-MS (ESI): m/z=455[M+H]⁺

Example 4532-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-N-(1-methyl-azetidin-3-yl)-isobutyramide453

To a solution of2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionicacid (0.350 g, 0.000753 mol) and oxalyl chloride (2M in methylenechloride, 0.38 mL, 0.0007534 mol) in dry methylene chloride (2.415 mL,0.03767 mol) was added 1 drop of N,N-dimethylformamide (0.02917 mL,0.0003767 mol). The solution was stirred for 1 h at room temperature andconcentrated in vacuo. The acid chloride was re-dissolved in methylenechloride (1.739 mL, 0.02712 mol) and added dropwise to a solution of1-methyl-azetidin-3-ylamine (0.1198 g, 0.0007534 mol) and triethylamine(0.3255 mL, 0.002336 mol) in methylene chloride (1.739 mL, 0.02712 mol).The reaction was stirred at room temperature for 3 h. Brine andmethylene chloride were added and the aqueous layer was extracted 3×with methylene chloride. The organic layers were combined, dried withMgSO₄, and concentrated. The crude was purified by reverse-phase HPLC togive 453 (90.1 mg) as a beige solid. MS(ESI+) 533.2. ¹H NMR (400 MHz,DMSO) δ 8.40 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H),7.76 (d, J=6.9, 1H), 7.51 (dd, J=8.3, 1.8, 1H), 7.40 (d, J=1.7, 1H),5.84 (sept, J=6.4, 1H), 4.39 (t, J=5.0, 2H), 4.25-4.15 (m, 1H), 3.46 (m,4H), 2.89 (t, J=7.3, 2H), 2.22 (s, 3H), 1.73 (s, 6H), 1.56 (d, J=6.6,6H)

Example 4548-{1-[2-(3,3-Difluoro-azetidine-1-sulfonyl)-ethyl]-azetidin-3-yl}-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene454

Following the procedure for 320,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 and 1-ethenesulfonyl-3,3-difluoro-azetidine were reacted togive 454 isolated as a white solid (139 mg, 84%). LCMS: R_(T)=8.30 min,[M+H]⁺=551. ¹H NMR δ (ppm) (CDCl₃): 8.32 (1H, d, J=8.18 Hz), 7.89 (1H,s), 7.08 (1H, dd, J=8.21, 1.87 Hz), 6.97 (1H, d, J=1.84 Hz), 5.93-5.83(1H, m), 4.38 (2H, t, J=5.05 Hz), 4.31 (4H, t, J=12.10 Hz), 3.76 (2H, t,J=6.86 Hz), 3.75-3.63 (1H, m), 3.43-3.36 (2H, m), 3.23 (2H, t, J=6.61Hz), 3.11 (2H, t, J=7.01 Hz), 2.92 (2H, t, J=7.00 Hz), 1.60 (6H, d,J=6.63 Hz)

Example 455(2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-sulfonyl}-ethyl)-dimethyl-amine455

To a suspension of8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(75 mg, 0.17 mmol) in IMS (2 mL) was added dimethylamine (2M in MeOH,158 μL, 0.32 mmol) and the reaction mixture was stirred for 72 hours.The mixture was concentrated in vacuo to low volume and partitionedbetween DCM and water. The layers were separated and the organic layerwas washed with water followed by brine, dried (Na₂SO₄) and concentratedin vacuo. The resultant residue was combined with a previous batch ofthe desired compound and purified by flash chromatography (SiO₂, 0-2%MeOH in DCM) to give 455 as a white solid (43 mg, 34%). LCMS: R_(T)=8.51min, [M+H]⁺=503. ¹H NMR δ (ppm) (CDCl₃): 8.36 (1H, d, J=8.20 Hz), 7.90(1H, s), 7.16 (1H, dd, J=8.24, 1.92 Hz), 7.03 (1H, d, J=1.88 Hz),5.93-5.83 (1H, m), 4.39 (2H, t, J=5.04 Hz), 4.26 (2H, t, J=8.23 Hz),4.10 (2H, t, J=7.33 Hz), 3.81-3.74 (1H, m), 3.40 (2H, t, J=5.05 Hz),3.22-3.14 (2H, m), 2.81 (2H, t, J=7.47 Hz), 2.29 (6H, s), 1.61 (6H, d,J=6.63 Hz)

Example 4564-Isopropyl-5-{8-[1-(3-methyl-oxetan-3-ylmethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-2,4-dihydro-[1,2,4]triazol-3-one456

Similarly to as described in General Procedure C,5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-onewas reacted with1-((3-methyloxetan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.Purification of the crude reaction mixture by reverse phase HPLC gave456. LCMS: 479.1

Example 4571-[3-(5-Chloro-2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidin-1-yl]-ethanone457

To a solution of3-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylicacid tert-butyl ester (90.0 mg, 0.179 mmol) in N,N-Dimethylformamide(3.35 mL, 43.3 mmol) was added N-Chlorosuccinimide (19 mg, 0.14 mmol)and 1.00 M of Hydrogen chloride in Water (0.018 mL). The reaction wasstirred at rt 4 h. the reaction was quenched with water then extractedwith EtOAc 3×. The organic layer was dried Na2SO4, concentrated. Thecrude product was purified by isco column to give3-(5-Chloro-2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylicacid tert-butyl ester (EtOAc/Hep eluted at 75%). MS: (ESI+)=483.1

3-(5-Chloro-2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylicacid tert-butyl ester was deprotected and acetylated to give 457 MS:(ESI+)=539.1. ¹H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3 Hz, 1H), 8.14 (s,1H), 7.92 (s, 1H), 7.39 (dd, J=8.3, 1.8 Hz, 1H), 7.31-7.27 (m, 2H),6.72-6.61 (m, 1H), 4.74-4.69 (m, 3H), 4.44-4.32 (m, 4H), 4.04 (s, 2H),3.40 (t, J=5.0 Hz, 2H), 1.84 (s, 3H), 1.10 (s, 6H)

Example 4591-(4-{2-[2-(2-Hydroxy-propyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-2-methyl-propan-2-ol459

Following the procedure for 114,1-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-olwas reacted with2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 459. MS(ESI+) 467.1. ¹H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3,1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.43 (dd, J=8.3, 1.8,1H), 7.30 (d, J=1.7, 1H), 4.95 (d, J=5.3, 1H), 4.82 (dd, J=13.3, 7.5,1H), 4.76-4.66 (m, 2H), 4.46-4.32 (m, 2H), 4.28-4.14 (m, 1H), 4.03 (s,2H), 3.44 (t, J=5.0, 2H), 1.16 (d, J=6.3, 3H), 1.10 (s, 6H)

Example 4602-Methyl-1-(4-{2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propan-2-ol460

Following the procedure for 114,8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 460. MS(ESI+) 522.2. ¹H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.3,1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.38 (dd, J=8.3, 1.7,1H), 7.30 (d, J=1.6, 1H), 4.95 (t, J=6.5, 2H), 4.72 (s, 1H), 4.39 (t,J=5.0, 2H), 4.04 (s, 2H), 3.45 (t, J=5.0, 2H), 3.43-3.38 (m, 4H), 2.82(t, J=6.5, 2H), 2.46-2.35 (m, 4H), 1.10 (s, 6H).

Example 461Oxetan-3-yl-[2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-amine461 Step 1:1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 G, 5.2mmol) in 30 mL of DMSO was added cesium carbonate (6.73 G, 20.6 mmol)and 2-chloroethylbromide (0.854 mL, 10.3 mmol). This reaction mixturewas stirred at room temperature for 4 hours. The reaction mixture wasthen diluted with a large volume of EtOAc. The organic was washed withwater×1, saline×1, then dried over Na2SO4 and conc. to give1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas a solid.

Step 2:8-[1-(2-chloro-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a solution of the8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 51 (2.00 g, 34.75 mmol) and1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein 8 mL of acetonitrile was added 7 mL of 2M of potassium carbonate inwater followed by the addition oftetrakis(triphenylphosphine)palladium(0) (0.55 G, 0.476 mmol). Thisreaction mixture was heated on a Biotage microwave at 140 C for 10minutes. The cooled reaction mixture was diluted with EtOAc, filtered toremove a black ppt, then washed with water×1, saline×1, then dried overNa2SO4, concentrated and purified by MPLC on a 12 gram silica column,eluting with 10-80% EtOAc/heptanes to give8-[1-(2-chloro-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(1.6 g) as a yellow powder.

Step 3

To a solution of8-[1-(2-chloro-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.200 g, 0.416 mmol) and 3-oxetanamine (0.608 g, 2.08 mmol) in 5 mL ofDMF was added potassium carbonate (0.287 g, 2.08 mmol) and potassiumiodide (0.069 g, 0.416 mmol). The reaction mixture was heated at 50° C.for approximately 4 hours. The heated was increased to 70 C and thereaction was continued another 15 hours to give the desired product asdetermined by LCMS. The crude material was purified by RP-HPLC tocleanly give 461. MS: (ESI+)=518.3

Example 4621-[4-(2-{2-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-2H-[1,2,4]triazol-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl)-pyrazol-1-yl]-2-methyl-propan-2-ol462

8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid1-dimethylamino-meth-(Z)-ylideneamide was reacted with4-Hydrazino-piperidine-1-carboxylic acid benzyl ester to give8-bromo-2-(2-piperidin-4-yl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.MS(ESI+) 432.0/434.0.

To a solution of8-bromo-2-(2-piperidin-4-yl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.216 g, 0.000500 mol) in methylene chloride (6.227 mL, 0.09715 mol)was added (tert-butyl-dimethyl-silanyloxy)-acetaldehyde (0.2855 mL,0.001499 mol) and acetic acid (0.002841 mL, 4.996E-5 mol) followed bysodium triacetoxyborohydride (0.3177 g, 0.001499 mol). The reaction wasstirred at room temperature for 5 hours.

The reaction was quenched with 1N NaOH. Methylene chloride was added andthe mixture was extracted 3 times with methylene chloride. The organicphases were combined, dried with MgSO₄ and concentrated. The mixture waspurified by flash chromatography (0-10% MeOH in DCM) to afford8-Bromo-2-(2-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(117 mg) as a white solid. MS(ESI+) 590.2/592.2.

Following the procedure for 114,8-Bromo-2-(2-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give1-{4-[2-(2-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol.MS(ESI+) 650.3

To a solution of1-{4-[2-(2-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol(0.150 g, 0.000231 mol) in methanol (2.0 mL, 0.049 mol) was addedhydrogen chloride (4N in dioxane, 1 mL, 0.00025 mol). The reaction wasstirred at room temperature overnight. The solvent was removed in vacuoand the crude was purified by reverse-phase HPLC to give 462 (31.1 mg)as a white solid. MS(ESI+) 536.2

Example 4631-Isopropyl-5-{8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H-[1,2,4]triazol-3-ylamine463

A suspension of(1-isopropyl-5-{8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H-[1,2,4]triazol-3-yl)-carbamicacid benzyl ester (157 mg, 0.25 mmol) in IMS (25 mL) was treated with aslurry of palladium on carbon (50 mg, 50% in water) and the mixture wasstirred under an atmosphere of hydrogen for 3 days. More palladium oncarbon was added and the mixture stirred for another 18 hours beforebeing filtered through celite. The filtrate was concentrated in vacuoand the residue purified by reverse-phase preparative HPLC (Gemini C₁₈column, gradient 10-90% MeOH in H₂O+0.1% HCO₂H) to give 463 as a whitesolid after freeze drying (43 mg, 35%). LCMS: R_(T)=6.30 min,[M+H]⁺=489. ¹H NMR δ (ppm) (DMSO-d6): 8.22 (1H, d, J=8.18 Hz), 7.14 (1H,dd, J=8.25, 1.81 Hz), 6.99 (1H, d, J=1.77 Hz), 5.67-5.59 (1H, m), 5.54(2H, s), 4.30 (2H, t, J=5.02 Hz), 3.63-3.50 (3H, m), 3.10 (4H, t, J=6.28Hz), 3.01 (3H, s), 2.78 (2H, t, J=6.83 Hz), 1.42 (6H, d, J=6.58 Hz). 2Protons obscured by water peak

Example 4642-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-N-methyl-isobutyramide464

Following the procedure of Example 319, a suspension of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (200 mg, 0.42 mmol) and 2-bromo-2,N-dimethyl-propionamidein cesium carbonate and DMF were reacted at 80° C. to give 464 isolatedas a white solid (33 mg, 17%). LCMS: R_(T)=7.62 min, [M+H]⁺=467. ¹H NMRδ (ppm) (DMSO-d6): 8.27 (1H, d, J=8.17 Hz), 8.06 (1H, s), 7.63 (1H, s),7.16 (1H, dd, J=8.20, 1.82 Hz), 6.96 (1H, s), 5.83-5.73 (1H, m), 4.32(2H, t, J=5.01 Hz), 3.53 (2H, s), 3.39 (2H, t, J=5.02 Hz), 2.58 (3H, d,J=4.63 Hz), 1.50 (6H, d, J=6.59 Hz), 1.06 (6H, s). 3 Protons obscured bywater peak

Example 4652-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanesulfonicacid methylamide 465

Following the procedure for 320,8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 and N-methyl ethene sulfonamide were reacted to give 465.LCMS: R_(T)=7.25 min, [M+H]⁺=489. ¹H NMR δ (ppm) (CDCl₃): 8.31 (1H, t,J=8.17 Hz), 7.89 (1H, s), 7.06 (1H, dd, J=8.21, 1.88 Hz), 6.97 (1H, d,J=1.83 Hz), 5.93-5.83 (1H, m), 4.91 (1H, s), 4.38 (2H, t, J=5.03 Hz),3.76 (2H, t, J=7.01 Hz), 3.72-3.62 (1H, m), 3.41-3.34 (2H, m), 3.25 (2H,t, J=6.71 Hz), 3.08-3.02 (2H, m), 2.99-2.91 (2H, m), 2.80 (3H, s), 1.60(6H, d, J=6.78 Hz)

Example 4662-(5-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-[1,2,4]triazol-1-yl)-propan-1-ol466

Following the procedure for 114,2-[5-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propylester was reacted with2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olto give 466. MS(ESI+) 467.1. ¹H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.3,1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.44 (dd, J=8.3, 1.8,1H), 7.30 (d, J=1.7, 1H), 5.86-5.74 (m, 1H), 4.95 (t, J=5.4, 1H), 4.72(s, 1H), 4.39 (t, J=5.2, 2H), 4.04 (s, 2H), 3.86 (ddd, J=10.9, 7.9, 5.7,1H), 3.78-3.71 (m, 1H), 3.44 (t, J=5.0, 2H), 1.50 (d, J=6.7, 3H), 1.10(s, 6H)

Example 4672-(4-{2-[2-(2-Morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol467

Following the procedure for 258,8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazoleto give 467. MS(ESI+) 494.1. ¹H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.3,1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.38 (dd, J=8.3, 1.7,1H), 7.30 (d, J=1.7, 1H), 4.95 (t, J=6.5, 2H), 4.91 (t, J=5.3, 1H), 4.39(t, J=5.0, 2H), 4.16 (t, J=5.7, 2H), 3.77 (q, J=5.6, 2H), 3.51-3.38 (m,6H), 2.82 (t, J=6.5, 2H), 2.46-2.36 (m, 4H)

Example 4681-(4-(2-(3-amino-1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol468

To a rapid stirred suspension of 2-Methyl-isothiourea (13.0 g, 144.1mmol) in DCM (200 mL) was added NaOH aqueous solution (100 mL, 2 N) Themixture was cooled to 0° C. in ice-water bath and then was added asolution of Boc₂O (8.6 g, 65 mmol) in DCM (50 mL) dropwise over 1 hour.After stirred for over night, the mixture was added water (100 mL). Theaqueous was separated and the organic was washed with water (50 mL×2).The organic layer was dried over anhydrous sodium sulfate, concentratedto afford 7.1 g of N-Boc-2-Methyl-isothiourea. Yield: 26%. ¹H NMR(CDCl₃, 400 MHz) δ: 2.44 (s, 3H), 1.49 (s, 9H). LC-MS: m/z=191 [M+H⁺]

A mixture 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylicacid (10.0 g, 30.3 mmol), EDCI (7.5 g, 36.4 mmol) in DCM (200 mL) wasstirred at room temperature for 10 min, then DMAP (7.39 g, 60.6 mmol)was added by one portion. 10 minutes later, N-Boc-2-Methyl-isothiourea(6.9 g, 36.4 mmol) was added. The reaction mixture was stirred at roomtemperature overnight. After removal of the solvent, the residue wastreated with methanol/water (20 mL, 1:1) to afford 10.2 g of methylN′-8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl-N-Boc-carbamimidothioate.Yield: 67%. ¹H NMR (CDCl₃, 400 MHz): δ12.33 (s, 1H), 7.95-7.51 (m, 2H),7.35-6.94 (m, 2H), 4.28-4.25 (m, 2H), 3.15-3.30 (m, 2H), 2.52 (s, 3H),1.51-1.45 (s, 9H). LC-MS: m/z=497 [M+H⁺]

A mixture ofN′-8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl-N-Boc-carbamimidothioate(100 mg, 0.2 mmol), DIPEA (260 mg, 2 mmol), isopropyl-hydrazine HCl salt(30 mg, 0.4 mmol) in DMF (5 mL) was stirred at 90° C. for 4 hours. Thereaction mixture was concentrated to dryness, and then purified bypre-TLC to afford 65 mg of5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-N-Boc-amine.Yield: 64%. ¹H NMR (CDCl₃, 400 MHz): δ7.48-7.46 (m, 1H), 7.20-7.16 (m,1H), 7.16-7.09 (m, 3H), 4.82-4.79 (m, 1H), 4.29-4.26 (m, 2H), 3.18-3.19(m, 2H), 1.52-1.50 (s, 6H), 1.45-1.40 (m, 9H). LC-MS: m/z=505 [M+H⁺]

A mixture of5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-N-Boc-amine(500 mg, 0.99 mmol), Pd(dppf)Cl₂(72 mg, 0.099 mmol), cesium carbonate(644 mg, 2.0 mmol),2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol(318 mg, 1.19 mmol) in DME-H₂O (15 mL, 3:1) was stirred at 80° C. underN₂ atmosphere overnight. After cooled down, the reaction mixture wasfiltered though a ceilite, concentrated and purified by column (elutedwith Hexanes:EtOAc=2:1) to give 110 mg (yield=20%) of Boc-protected 468and about 20 mg of 468. Boc-protected 468 (110 mg, 0.2 mmol) wasdissolved in methanol, and HCl-methanol (4 mol/L, 20 mL) was addeddropwise. The mixture was stirred for over night, concentrated andpurified by pre-TLC to afford 70 mg of 468, yield: 76%. ¹H NMR (CDCl₃,400 MHz): δ7.77 (s, 1H), 7.64-7.70 (m, 2H), 7.26 (s, 1H), 7.13-7.11 (m,2H), 4.81-4.74 (m, 1H), 4.32-4.30 (m, 2H), 4.04 (s, 2H), 3.23-3.20 (m,2H), 1.51-1.48 (m, 6H), 1.52-1.50 (s, 6H), 1.18-1.14 (m, 6H). LC-MS:m/z=464 [M+H⁺]

Example 4692-Amino-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propan-1-one469

To a solution of(2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamicacid tert-butyl ester (203 mg, 0.36 mmol) in DCM (2 mL) was added TFA (2mL) and the reaction mixture was stirred for 1 hour then concentrated invacuo. The residual solid was triturated with ether, filtered off andair-dried before being dissolved in DCM. The organic solution was washed(aqueous saturated sodium bicarbonate solution, followed by water andthen brine), dried (MgSO₄) and concentrated in vacuo. The residue wasfreeze-dried from MeOH/H₂O to give 469 as a white solid (116 mg, 71%).LCMS: R_(T)=8.13 min, [M+H]⁺=453. ¹H NMR δ (ppm) (DMSO-d6): 8.30 (1H, d,J=8.19 Hz), 8.06 (1H, s), 7.18 (1H, dd, J=8.24, 1.86 Hz), 7.00 (1H, d,J=1.82 Hz), 5.82-5.74 (1H, m), 4.79 (1H, s), 4.42 (1H, s), 4.33 (2H, t,J=5.13 Hz), 4.19 (1H, s), 3.77-3.70 (2H, m), 3.39 (2H, t, J=5.02 Hz),1.74 (2H, s), 1.50 (6H, d, J=6.59 Hz), 1.17 (6H, s)

Example 470N-Isopropyl-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide470

Following the procedure of 319, a suspension of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (200 mg, 0.42 mmol) and N-isopropyl-2-chloroacetamide gave470 isolated as a yellow solid (91 mg, 26%). LCMS: R_(T)=3.31 min,[M+H]⁺=467. ¹H NMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.18 Hz), 8.05 (1H,s), 7.40 (1H, d, J=8.06 Hz), 7.17 (1H, dd, J=8.24, 1.83 Hz), 6.99 (1H,d, J=1.78 Hz), 5.83-5.73 (1H, m), 4.35-4.29 (2H, m), 3.86-3.80 (1H, m),3.69-3.58 (3H, m), 3.41-3.35 (2H, m), 3.18 (2H, d, J=6.73 Hz), 3.00 (2H,s), 1.50 (6H, d, J=6.59 Hz), 1.03 (6H, d, J=6.59 Hz)

Example 4712-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1-morpholin-4-yl-ethanone471

Following the procedure of 319, a suspension of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 (200 mg, 0.42 mmol) and 4-(2-chloroacetyl)morpholine gave471 isolated as a yellow solid (79 mg, 22%). LCMS: R_(T)=3.17 min,[M+H]⁺=495. ¹H NMR δ (ppm) (DMSO-d6): 8.25 (1H, d, J=8.17 Hz), 8.05 (1H,s), 7.17 (1H, dd, J=8.24, 1.82 Hz), 7.03 (1H, d, J=1.77 Hz), 5.82-5.73(1H, m), 4.35-4.29 (2H, m), 3.67-3.56 (2H, m), 3.58-3.45 (5H, m),3.44-3.34 (6H, m), 3.31 (2H, s), 3.16 (2H, t, J=6.11 Hz), 1.50 (6H, d,J=6.59 Hz)

Example 472N-(2-Hydroxy-2-methyl-propyl)-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide472

A solution of{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-aceticacid TFA salt (228 mg, 0.42 mmol), EDCI (97 mg, 0.50 mmol) and HOBT (68mg, 0.50 mmol) in THF (3 mL) was stirred for 20 minutes.1-Amino-2-methyl-propan-2-ol (42 mg, 0.47 mmol) anddiisopropylethylamine (0.18 mL, 1.05 mmol) in THF (2 mL) were added andthe reaction mixture was stirred at RT for 18 hours. Another portion of1-amino-2-methyl-propan-2-ol, EDCI, HOBT, DIPEA and THF (1.5 mL) wasadded and the reaction mixture was warmed at 45° C. for 3 hours. Aqueoussaturated sodium bicarbonate solution was added and the mixture wasextracted with DCM (×2). The combined organic extracts were dried(MgSO₄), concentrated in vacuo and the residue purified by flashchromatography (SiO₂, 0-10% MeOH in DCM) to give 472 as a white solid(92 mg, 44%). LCMS: R_(T)=3.14 min, [M+H]⁺=497. ¹H NMR δ (ppm)(DMSO-d6): 8.26 (1H, d, J=8.18 Hz), 8.06 (1H, s), 7.44 (1H, t, J=6.04Hz), 7.19 (1H, dd, J=8.24, 1.80 Hz), 7.01 (1H, d, J=1.75 Hz), 5.82-5.74(1H, m), 4.51 (1H, s), 4.32 (2H, t, J=5.03 Hz), 3.73-3.60 (3H, m), 3.39(2H, t, J=5.06 Hz), 3.26-3.16 (2H, m), 3.10 (2H, s), 3.02 (2H, d, J=6.03Hz), 1.50 (6H, d, J=6.59 Hz), 1.01 (6H, s)

Example 4734-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one473

A microwave vial was charged with an approximately 1:1 mixture of4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-oneand4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2,5-dimethyl-2,4-dihydro-[1,2,4]triazol-3-one(41 mg),2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol(33 mg, 0.13 mmol), PdCl₂(dppf)₂.DCM (3.5 mg, 0.004 mmol), cesiumcarbonate (68 mg, 0.21 mmol), THF (1 mL) and water (0.2 mL). The vialwas sealed and the mixture evacuated and purged with argon (×3). Thereaction mixture was heated at 80° C. for 17 hours then a further2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol(15 mg) and PdCl₂(dppf)₂.DCM (4 mg) were added, the vial was re-filledwith argon as before and stirring at 80° C. was continued for a further20 hours. After cooling the reaction mixture was concentrated in vacuo.The resultant residue was purified by flash chromatography (SiO₂, 0-4%MeOH in DCM) to give 473 as a white solid (12 mg, 27%). LCMS: R_(T)=4.14min, [M+H]⁺=453. ¹H NMR δ (ppm) (DMSO-d6): 8.14 (1H, d, J=8.26 Hz), 8.08(1H, s), 7.87 (1H, s), 7.33 (1H, dd, J=8.26, 1.84 Hz), 7.22 (1H, d,J=1.82 Hz), 4.68 (1H, s), 4.31 (2H, t, J=5.01 Hz), 3.98 (2H, s), 3.35(3H, s), 3.28 (2H, m), 2.65 (3H, s), 1.04 (6H, s)

Example 4744-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one474

Following the procedure for 473, a mixture of4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-oneand4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-oneand2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-olwere reacted to give 474 isolated as a white solid (34 mg, 59%). LCMS:R_(T)=4.79 min, [M+H]⁺=481. ¹H NMR δ (ppm) (DMSO-d6): 8.15 (1H, d,J=8.26 Hz), 8.08 (1H, s), 7.87 (1H, d, J=0.74 Hz), 7.33 (1H, dd, J=8.26,1.84 Hz), 7.22 (1H, d, J=1.82 Hz), 4.68 (1H, s), 4.38-4.28 (3H, m), 3.99(2H, s), 3.28 (2H, m), 2.67 (3H, s), 1.29 (6H, t, J=6.68 Hz), 1.05 (6H,s)

Example 4752-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-acetamide475

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 375 (250 mg, 0.49 mmol) in DCM (2.5 mL) was added triethylamine(157 μL, 1.13 mmol) followed by 2-bromoacetamide (81 mg, 0.59 mmol). Thereaction mixture was stirred for 42 hours before being diluted with MeOHand water. The DCM was removed in vacuo to give a suspension. The solidwas filtered off and washed with MeOH then ether to give 475 as anoff-white solid (160 mg, 72%). LCMS: R_(T)=3.17 min, [M+H]⁺=453. ¹H NMRδ (ppm) (DMSO-d6): 8.23 (1H, d, J=8.20 Hz), 8.05 (1H, s), 7.17 (1H, s),7.08 (1H, s), 7.07-7.02 (1H, m), 6.90 (1H, d, J=1.75 Hz), 5.81-5.71 (1H,m), 4.35-4.28 (2H, m), 3.37 (2H, s), 2.90-2.79 (4H, m), 2.13 (2H, dd,J=8.92, 8.51 Hz), 1.77-1.67 (4H, m), 1.50 (6H, d, J=6.58 Hz). 1 Protonobscured by solvent peaks

Example 4762-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene476

Following the procedure for 320,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 375 and methyl vinyl sulfone were reacted, with added DCM toaid dissolution. Addition of a mixture of methanol, ethanol and waterfollowed by removal in vacuo of the DCM precipitated the product fromthe reaction mixture. The resulting solid was collected by filtration togive 476 as an off-white solid (175 mg, 71%). LCMS: R_(T)=3.30 min,[M+H]⁺=502. ¹H NMR δ (ppm) (DMSO-d6): 8.23 (1H, d, J=8.20 Hz), 8.05 (1H,s), 7.05 (1H, dd, J=8.25, 1.78 Hz), 6.89 (1H, d, J=1.74 Hz), 5.82-5.72(1H, m), 4.33-4.27 (2H, m), 3.37 (2H, t, J=5.06 Hz), 3.02 (3H, s), 2.97(2H, s), 2.70 (2H, s), 2.03 (2H, s), 1.75 (2H, d, J=12.38 Hz), 1.67-1.55(2H, m), 1.50 (6H, d, J=6.59 Hz). 3 Protons obscured by solvent peaks

Example 4773-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1-(2-methoxy-ethyl)-1H-pyridin-2-one477

To 330 (0.075 g, 0.18 mmol) in DMF (2 mL) was added1-bromo-2-methoxyethane (0.1 mL, 0.55 mmol) and cesium fluoride (0.084g, 0.55 mmol). The reaction mixture was allowed to stir and heat at 80°C. for 2 days while monitoring by LCMS. To the reaction mixture wasadded bromo-2-methoxyethane (1 mL, 7.2 mmol) and cesium fluoride (1.0 g,6.6 mmol). The reaction mixture was allowed to stir and heat at 80° C.for 2 days before cooling, concentrating under reduced pressure, anddiluting with EtOAc. The solution was washed sequentially with water,and brine, before drying over MgSO₄ and concentrating under reducedpressure. The crude material was dissolved in DMF and purified byreverse phase HPLC to provide 477 (21 mg, 24%). ¹H NMR (400 MHz, DMSO) δ9.08 (d, J=2.3, 1H), 8.10 (s, 1H), 7.73-7.55 (m, 3H), 7.08 (d, J=8.4,1H), 6.34 (t, J=6.9, 1H), 5.95 (dt, J=13.1, 6.5, 1H), 4.40 (t, J=4.9,2H), 4.16 (t, J=5.3, 2H), 3.66 (t, J=5.3, 2H), 3.46 (t, J=5.0, 2H), 3.27(s, 3H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 464.1 (M+H)

Example 4782-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-[2-(2-methoxy-ethoxy)-pyridin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene478

To 330 (0.075 g, 0.18 mmol) in DMF (2 mL) was added1-bromo-2-methoxyethane (0.1 mL, 0.55 mmol) and cesium fluoride (0.084g, 0.55 mmol). The reaction mixture was allowed to stir and heat at 80°C. for 2 days while monitoring by LCMS. To the reaction mixture wasadded bromo-2-methoxyethane (1 mL, 7.2 mmol) and cesium fluoride (1.0 g,6.6 mmol). The reaction mixture was allowed to stir and heat at 80° C.for 2 days before cooling, concentrating under reduced pressure, anddiluting with EtOAc. The solution was washed sequentially with water,and brine, before drying over MgSO₄ and concentrating under reducedpressure. The crude material was dissolved in DMF and purified byreverse phase HPLC to provide 478 (5 mg, 6%). ¹H NMR (400 MHz, DMSO) δ8.60 (d, J=2.3, 1H), 8.16 (dd, J=4.9, 1.8, 1H), 8.10 (s, 1H), 7.80 (dd,J=7.4, 1.8, 1H), 7.59 (dd, J=8.4, 2.3, 1H), 7.13 (dd, J=7.7, 5.0, 2H),5.73 (dt, J=13.1, 6.6, 1H), 4.51-4.38 (m, 4H), 3.70-3.58 (m, 2H), 3.48(t, J=5.0, 2H), 3.18 (d, J=14.6, 3H), 1.55-1.46 (m, 6H). MS (ESI(+)):m/z 464.1 (M+H)

Example 4793-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1,4,4-trimethyl-imidazolidin-2-one479 Step 1:1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2-one

A mixture of 0.254 g (0.65 mmol) of1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-onefrom Example 429, and 50.0 mg (1.25 mmol) of 60% sodium hydridedispersion in mineral oil in 2 ml of tetrahydrofuran and 2 ml ofdimethylformamide was stirred for 20 min. 0.062 ml (1.00 mmol) of methyliodide was added in one portion to the above mixture. The mixture wasstirred for 30 min and poured into 10 ml of 1 N aq hydrochloric acid.The mixture was extracted with ethyl acetate. The organic extracts werewashed with water, brine, dried over magnesium sulfate and concentratedin vacuum. The residue was triturated with hexane and the resultingprecipitate was filtered and washed with hexane. Yield 260 mg (98%).MS(ESI+): 408.1

Step 2

1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2-onewas coupled with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olto give 479. Yield 33%. MS(ESI):468.2. 1H NMR (400 MHz, DMSO) δ 8.17 (d,J=8.2, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.36 (dd, J=8.2, 1.8, 1H), 7.22(d, J=1.7, 1H), 4.73 (s, 1H), 4.31 (t, J=4.9, 2H), 4.03 (s, 2H), 3.35(d, J=5.6, 2H), 3.19 (t, J=5.0, 2H), 2.83 (s, 3H), 1.72 (s, 6H), 1.09(s, 6H)

Example 4801-(3-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidin-1-yl)-2-methyl-propan-2-ol480

Following the procedure for 114,8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with3-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-azetidine-1-carboxylicacid tert-butyl ester to give3-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylicacid tert-butyl ester which was treated with acid via General ProcedureF to give8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.

To a slurry of8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.232 g, 0.000519 mol) in methanol (3.0 mL, 0.074 mol) was addedN,N-Diisopropylethylamine (0.108 mL, 0.000623 mol) then isobutyleneoxide (0.330 mL, 0.0037 mol). The reaction was stirred at roomtemperature overnight. The solvent was removed in vacuo and purified byreverse-phase HPLC to give 480 (24.3 mg) as a colorless solid. MS(ESI+)520.2. ¹H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.31 (d, J=8.3, 1H), 8.01(s, 1H), 7.47 (dd, J=8.3, 1.8, 1H), 7.35 (d, J=1.8, 1H), 5.86-5.68 (m,1H), 4.97 (p, J=6.9, 1H), 4.39 (t, J=5.0, 2H), 4.11 (s, 1H), 3.79 (dd,J=8.0, 7.3, 2H), 3.49 (dd, J=8.0, 6.8, 2H), 3.44 (t, J=5.0, 2H), 2.44(s, 2H), 2.32 (s, 3H), 1.53 (d, J=6.6, 6H), 1.08 (s, 6H).

Example 4812-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-oxazol-2-ylmethyl-azetidin-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene481

Following the procedure for 423, a suspension of8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 235 and oxazole-2-carbaldehyde were reacted. The crude productwas purified by flash chromatography (SiO₂, 0-6% 2N NH₃/MeOH in DCM) togive an oil. The oil was triturated with ether, the resulting solidfiltered off and washed with ether to give 481 as a cream solid (81 mg,44%). LCMS: R_(T)=3.21 min, [M+H]⁺=449. ¹H NMR δ (ppm) (CDCl₃): 8.30(1H, d, J=8.18 Hz), 7.89 (1H, s), 7.62 (1H, d, J=0.84 Hz), 7.08 (1H, dd,J=8.21, 1.86 Hz), 7.06 (1H, d, J=0.83 Hz), 6.96 (1H, d, J=1.83 Hz),5.93-5.84 (1H, m), 4.38 (2H, t, J=5.06 Hz), 3.87 (2H, t, J=7.32 Hz),3.80 (2H, s), 3.78-3.69 (1H, m), 3.41-3.34 (4H, m), 1.60 (6H, d, J=6.63Hz)

Example 482 phosphoric acidmono-(2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethyl)ester 482

Phosphoric acid dibenzyl ester2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethylester (180 mg, 0.26 mmol) was dissolved in methanol:EtOAc (1:1, 6 mL)and the solution was flushed with bubbling nitrogen. Palladium hydroxide(5% on carbon, 40 mg) was added and the reaction mixture was placedunder hydrogen atmosphere (1 atm, balloon) overnight while rapidlystirred. Filtration over celite and concentration of the filtrate gave482. Lyophilization of a solution in acetonitrile and 1% NH₄OH in watergave 482 as the bis-ammonium salt.

Example 4832-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-isobutyramide483

2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile(346 mg, ˜50% pure, ˜0.40 mmol) was treated with concentrated sulphuricacid (5 mL) and the mixture was stirred for 5.5 hours then diluted withice chips (˜50 mL) and made basic with solid sodium carbonate. Themixture was extracted with 10% MeOH in DCM (×4) and the combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The resultantresidue was purified by flash chromatography (SiO₂, 0-5% MeOH in DCMfirst time then 0-100% EtOAc in DCM) to give 483 as a white solid (36mg, 19%). LCMS: R_(T)=3.28 min, [M+H]⁺=481. ¹H NMR δ (ppm) (DMSO-d6):9.54 (1H, s), 8.27 (1H, d, J=8.13 Hz), 8.05 (1H, s), 7.98 (1H, s), 7.86(1H, s), 7.05 (1H, d, J=8.29 Hz), 6.90 (1H, s), 5.81-5.73 (1H, m), 4.32(2H, s), 3.41-3.30 (4H, m), 3.12 (1H, m), 2.83 (1H, m), 2.13 (2H, d,J=13.80 Hz), 1.99 (1H, d, J=13.56 Hz), 1.72 (1H, s), 1.50 (12H, d,J=6.50 Hz). 1 Proton obscured by water peak

Example 484diethyl-[2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-amine484

To a reaction vial charged with2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol150 (0.250 g, 0.540 mmol) was added 4 mL DCM to give a slurry. Next,Dess-Martin periodinane(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 0.2522 g, 0.594mmol) was added portion-wise and the reaction mixture was stirred atroom temperature with LCMS monitor. Full conversion was seen after 30minutes reaction time. The reaction mixture was diluted with water togive a white precipitate. This solid was collected by vacuum filtration,washed with EtOAc and dried on high vacuum to give the intermediatealdehyde,2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanal.To a suspension of the aldehyde (0.160 g, 0.347 mmol) and diethylamine(0.127 g, 1.74 mmol) in 1.0 ml of DCM was added acetic acid (0.0198 mL,0.347 mmol) and the reaction mixture was heated at 40 C for 1 hour.Finally sodium cyanoborohydride (0.0350 g, 0.556 mmol) was added inportions. The reaction mixture was heated at 40° C. for 45 minutes withcomplete conversion to product as determined by LCMS. The cooledreaction mixture was diluted with DCM, washed with water and saline, andconcentrated to a solid which was purified by RP-HPLC to give 484. MS:(ESI+)=518.2

Example 4851-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-5,5-dimethyl-imidazolidine-2,4-dione485 Step 1: 2-Bromo-2-methylpropanoyl isocyanate

Oxalyl chloride (0.61 ml, 7.2 mmol) was added to a mixture of 0.996 g(6.00 mmol)2-bromo-2-propionamide in 35 ml of dichloroethane. Themixture was stirred at room temperature for 1 hr. The mixture wasstirred at room temperature for 1 h hour and then heated at 85° C. for 4hours. The mixture was concentrated in vacuum 6.5 kPa at 37° C. giving1.25 g of 2-Bromo-2-methylpropanoyl isocyanate which was then usedwithout further purification.

Step 2:2-Bromo-2-methyl-N-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)carbamoylpropanamide

A mixture of 1250 mg (4.20 mmol) of2-amino-8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine intetrahydrofuran (6.75 mL, 83.2 mmol) was mixed with 1.25 g (6.00 mmol,1.42 eq.) of crude 2-bromo-2-methylpropanoyl isocyanate and stirred for20 hours. The precipitate was filtered off, washed with ethyl ether anddried on air to give2-Bromo-2-methyl-N-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)carbamoylpropanamide.Weight 2.21 g (75%). MS(ESI+): 488.0

Step 3:1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione

A mixture of 1.002 g (2.048 mmol) of2-bromo-2-methyl-N-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)carbamoylpropanamideand 1.660 g (5.11 mmol) of cesium carbonate in 100 ml ofN,N-Dimethylformamide was stirred at 60° C. for 2 hours. The mixture wasfiltered, the filtrate concentrated in high vacuum, the residuepartitioned between ethyl acetate and water. pH was adjusted to 5 byaddition of 5% aq citric acid. The organic extracts were washed withwater, brine, dried over MgSO4 and concentrated in vacuum to give1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dioneas an off-white powder which was used in the next steps without furtherpurification. Yield 0.812 g (97%). MS(ESI+): 408.1

Step 4

1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dionewas coupled with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olunder Suzuki conditions to give 485. Yield 12% MS (ESI+): 468.2. 1H NMR(400 MHz, DMSO) δ 11.86 (s, 1H), 8.16 (t, J=8.8, 1H), 8.12 (s, 1H), 7.91(s, 1H), 7.38 (dd, J=8.2, 1.8, 1H), 7.24 (d, J=1.8, 1H), 4.73 (s, 1H),4.33 (t, J=4.9, 2H), 4.03 (s, 2H), 3.25 (t, J=5.0, 2H), 1.78 (s, 6H),1.09 (s, 6H)

Example 4862-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-imidazol-1-yl}-ethanol486

A solution of8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 (0.100 g, 0.000256 mol) and potassium acetate (0.07524 g, 0.0007667mol) in dimethyl sulfoxide (0.8343 mL, 0.01176 mol) in a round bottomflask equipped with a magnetic stir bar was thoroughly purged withnitrogen. Bispinacol ester boronate (0.07139 g, 0.0002811 mol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.02087 g, 2.556E-5 mol) were added and thereaction was heated to 85° C. under inert atmosphere overnight. Themixture was partitioned between water and methylene chloride and themixture was extracted 3× with methylene chloride. The organic phaseswere combined, dried with MgSO₄ and concentrated. The whole was loadedonto silica and purified by flash chromatography (0-10% MeOH in DCM) togive2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(89 mg) as a yellow solid. MS(ESI+) 439.2.

Following the procedure for 258,4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazole was reactedwith2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneto give 486. MS(ESI+) 423.1. ¹H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3,1H), 8.11 (s, 1H), 7.73 (d, J=1.0, 1H), 7.68 (d, J=0.9, 1H), 7.58 (dd,J=8.3, 1.7, 1H), 7.44 (d, J=1.7, 1H), 5.95-5.74 (m, 1H), 5.00 (t, J=5.2,1H), 4.39 (t, J=5.0, 2H), 4.03 (t, J=5.4, 2H), 3.70 (q, J=5.3, 2H), 3.44(t, J=5.0, 2H), 1.56 (d, J=6.6, 6H)

Example 4878-(2-Fluoro-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene487

Following the procedure for 128,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand 2-fluoropyridin-3-ylboronic acid were reacted to give 487 (0.226 g,20%). ¹H NMR (400 MHz, DMSO) δ 8.48 (d, J=8.3, 1H), 8.33-8.18 (m, 2H),8.12 (s, 1H), 7.54-7.45 (m, 2H), 7.37 (d, J=1.5, 1H), 5.96-5.75 (m, 1H),4.44 (t, J=5.0, 2H), 3.49 (t, J=5.0, 2H), 1.90-1.28 (m, 6H). MS(ESI(+)): m/z 408.12 (M+H)

Example 4883-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-1H-pyridin-2-one488

Following the procedures for 330, 487 was treated with HCl to give 4880.086 g, 37%. ¹H NMR (400 MHz, DMSO) δ 11.87 (s, 1H), 8.35 (d, J=8.3,1H), 8.12 (d, J=4.0, 1H), 7.79 (dd, J=7.0, 2.0, 1H), 7.67-7.58 (m, 2H),7.42 (d, J=5.9, 1H), 6.32 (t, J=6.7, 1H), 5.85 (dt, J=13.1, 6.5, 1H),4.41 (dd, J=13.4, 8.4, 2H), 3.46 (t, J=5.0, 2H), 1.56 (d, J=6.6, 6H). MS(ESI(+)): m/z 406.1 (M+H)

Example 4891-Isopropyl-3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H-pyridin-2-one489

Following the procedure for 477, compound 330 and 2-iodopropane werereacted to give 489 (0.018 g, 12%). ¹H NMR (400 MHz, DMSO) δ 9.06 (d,J=2.3, 1H), 8.20-8.01 (m, 1H), 7.77 (dd, J=6.9, 1.9, 1H), 7.62 (ddd,J=10.8, 7.7, 2.2, 2H), 7.08 (d, J=8.4, 1H), 6.41 (t, J=6.9, 1H),6.11-5.79 (m, 1H), 5.20 (dt, J=13.8, 6.9, 1H), 4.55-4.22 (m, 2H), 3.46(t, J=5.0, 2H), 1.56 (t, J=7.5, 6H), 1.36 (d, J=6.8, 6H). MS (ESI(+)):m/z 448.2 (M+H)

Example 490(S)-2-Hydroxy-1-{3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-one490

Zinc (0.9862 g, 0.01508 mol) was stirred in 5 mL of degassedN,N-dimethylacetamide under N₂ atmosphere. Chlorotrimethylsilane (0.164mL, 0.00129 mol) and 1,2-dibromoethane (0.0928 mL, 0.00108 mol) wereadded and the mixture was stirred for 15 minutes.3-Iodo-azetidine-1-carboxylic acid tert-butyl ester (3.05 g, 0.0108 mol)in degassed N,N-dimethylacetamide (24.00 mL, 0.2581 mol) was addedslowly and the cloudy reaction was stirred at room temperature for 1.5h.

A solution of8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(2.704 g, 0.006671 mol) in N,N-dimethylacetamide (20 mL, 0.2 mol) wasdegassed with N₂ for 5 minutes.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.2729 g, 0.0003342 mol) and copper(I)iodide (0.1270 g, 0.0006671 mol) were added followed by the zincsolution prepared above (0.37M in DMA, 21.6 mL, 0.008006 mol). Thereaction was heated to 80° C. overnight. Saturated ammonium chloride andmethylene chloride were added and the mixture was filtered throughcelite and extracted 3× with methylene chloride. The organic phases werecombined, dried with MgSO₄ and concentrated. The crude product waspurified by flash chromatography (0-10% MeOH in methylene chloride) togive3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester. MS(ESI+) 482.2

3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester was treated with acid to give8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.MS(ESI+) 382.2.

To a solution of8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.811 g, 0.000786 mol) and N,N-diisopropylethylamine (0.274 mL, 0.00157mol) in tetrahydrofuran (5.0 mL, 0.062 mol) was added simultaneouslyL-lactic acid (0.0708 g, 0.000786 mol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.329 g, 0.000865 mol). The reaction was stirred atroom temperature overnight. The mixture was partitioned betweensaturated sodium bicarbonate and methylene chloride and extracted 3times with methylene chloride. The organic phases were combined, driedwith MgSO₄, and concentrated. The crude was purified by reverse-phaseHPLC to give 490 (191.2 mg) as a colorless solid. MS(ESI+) 454.2. ¹H NMR(400 MHz, DMSO) δ 8.34 (d, J=8.2, 1H), 7.22 (m, 1H), 7.06 (s, 1H),5.84-5.66 (m, 1H), 5.09 (dd, J=11.1, 5.8, 1H), 4.65 (m, 1H), 4.37 (t,J=5.0, 2H), 4.28 (m, 2H), 4.16 (quin, J=6.5, 1H), 3.94-3.78 (m, 2H),3.43 (t, J=5.0, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H), 1.21 (d, J=6.7,3H)

Example 4912-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene491

To a solution of8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.811 g, 0.000786 mol) in ethanol (4.0 mL, 0.068 mol) was added methylvinyl sulfone (0.0703 mL, 0.000786 mol) via syringe. The reaction wasstirred at room temperature overnight. The mixture was partitionedbetween saturated sodium bicarbonate and methylene chloride andextracted 3 times with methylene chloride. The organic phases werecombined, dried with MgSO₄, and concentrated. The crude was purified byreverse-phase HPLC to give 491 (213.4 mg) as a colorless solid. MS(ESI+)488.2. ¹H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2, 1H), 7.20 (dd, J=8.3,1.7, 1H), 7.05 (d, J=1.6, 1H), 5.85-5.64 (m, 1H), 4.36 (t, J=5.0, 2H),3.62 (m, 3H), 3.42 (t, J=5.0, 2H), 3.15 (m, 4H), 3.06 (s, 3H), 2.85 (m,2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H)

Example 4921-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-3,5,5-trimethyl-imidazolidine-2,4-dione492 Step 1:1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dione

A mixture of 204 mg (0.50 mmol) of1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione,0.0411 ml (0.66 mmol) of methyl iodide and 244 mg (0.750 mmol) of CesiumCarbonate in 5.0 ml of N,N-Dimethylformamide was heated at 80° C. for 2hours. The mixture was filtered, the filtrate concentrated in highvacuum, the residue partitioned between ethyl acetate and water. Theorganic extracts were washed with water, brine, dried over MgSO4 andconcentrated to give1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dione.Weight 0.205 (97%). MS(ESI+): 421.9

Step 2

1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dionewas coupled with2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olunder Suzuki palladium conditions to give 492. Yield 12%.MS(ESI+):482.2. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.3, 1H), 8.12 (s,1H), 7.91 (s, 1H), 7.39 (dd, J=8.3, 1.8, 1H), 7.24 (t, J=4.4, 1H), 4.73(s, 1H), 4.34 (t, J=4.9, 2H), 4.03 (s, 2H), 3.26 (t, J=5.0, 2H), 3.02(s, 3H), 1.81 (s, 6H), 1.09 (s, 6H)

Example 4931-(4,5-Dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-5,5-dimethyl-imidazolidine-2,4-dione493

A mixture of 49 mg (0.12 mmol) of1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dionefrom Example 485, and 0.0334 ml (0.24 mmol) of triethylamine in 5 ml ofethanol was hydrogenated over 120 mg of 10% palladium on charcoal at 1atm for 3 hours. The mixture was filtered through celite andconcentrated in vacuum. The residue was purified on 4 g siligal columneluting the product with ethyl acetate gradient in heptane to give 493.Yield 20 mg (51%). MS(ESI+): 330.1

Example 494(S)-3-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propane-1,2-diol494

To a solution of8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.311 g, 0.000816 mol) in methylene chloride (4.5 mL, 0.070 mol) wasadded acetone D-glyceraldehyde (0.319 g, 0.00245 mol) and acetic acid(2.5 mL, 0.044 mol) followed by sodium triacetoxyborohydride (0.519 g,0.00245 mol). The reaction was stirred at room temperature overnight,then quenched with 1N NaOH until basic. Methylene chloride was added andthe mixture was extracted 3 times with methylene chloride. The organiclayers were combined, dried with MgSO₄ and concentrated.

The crude was redissolved in methanol (4 mL, 0.1 mol). Hydrogen chloride(4N in dioxanes, 0.82 mL, 0.00326 mol), was added slowly and the mixturewas stirred at room temperature for 2 h. The solvent was removed invacuo and the crude was partitioned between 1N NaOH and methylenechloride and extracted 3 times with methylene chloride. The organiclayers were combined, dried with MgSO₄ and concentrated. The crude waspurified by reverse-phase HPLC to give 494 (204.2 mg) as a white solid.MS(ESI+) 456.2

Example 4959-(6-Fluoro-pyridin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene495

Following the procedure for 128,9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 and 6-fluoropyridin-3-ylboronic acid were reacted to give495 (0.346 g, 30%). ¹H NMR (500 MHz, DMSO) δ 8.68 (d, J=2.3, 1H), 8.55(s, 1H), 8.28 (td, J=8.3, 2.5, 1H), 8.13 (s, 1H), 7.68 (dd, J=8.4, 2.3,1H), 7.35 (dd, J=8.6, 2.7, 1H), 7.22 (d, J=8.4, 1H), 5.77 (dt, J=13.1,6.6, 1H), 4.43 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 1.51 (dd, J=54.9,6.6, 6H). MS (ESI(+)): m/z 408.1 (M+H)

Example 4965-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H-pyridin-2-one496

Following the procedures for Example 330, 495 was treated with HCl togive 496 (0.271 g, 81%). ¹H NMR (500 MHz, DMSO) δ 11.88 (s, 1H), 8.50(d, J=2.2, 1H), 8.12 (s, 1H), 7.82 (dd, J=9.5, 2.6, 1H), 7.65 (s, 1H),7.50 (dd, J=8.4, 2.2, 1H), 7.12 (d, J=8.4, 1H), 6.49 (d, J=9.5, 1H),5.79 (dt, J=13.1, 6.5, 1H), 4.39 (t, J=4.8, 2H), 3.46 (t, J=4.8, 2H),1.58 (d, J=6.6, 6H). MS (ESI(+): m/z 406.2 (M+H)

Example 4983-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1-(2-morpholin-4-yl-ethyl)-1H-pyridin-2-one498

Following the procedure for 477, compound 330 and4-(2-chloroethyl)morpholine hydrochloride were reacted to give 498(0.005 g, 2%). ¹H NMR (500 MHz, DMSO) δ 9.09 (d, J=2.3, 1H), 8.09 (s,1H), 7.72-7.66 (m, 2H), 7.61 (dd, J=8.4, 2.3, 1H), 7.08 (d, J=8.4, 1H),6.35 (t, J=6.9, 1H), 5.95 (dt, J=13.1, 6.5, 1H), 4.40 (t, J=5.0, 2H),4.10 (t, J=6.5, 2H), 3.60-3.53 (m, 4H), 3.46 (t, J=5.0, 2H), 2.64 (t,J=6.5, 2H), 2.46 (d, J=4.4, 4H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z519.2 (M+H)

Example 4992-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-ethanesulfonicacid dimethylamide 499

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneTFA salt 375 (188 mg, 0.37 mmol) and triethylamine (0.18 mL, 1.3 mmol)in IMS (3 mL) was added ethenesulfonic acid dimethylamide and thereaction mixture stirred at RT for 18 h before being concentrated invacuo. The resultant residue was subjected to flash chromatography(SiO₂, gradient 0 to 5% MeOH in DCM) to give 499 as a beige solid (145mg, 74%). LCMS: R_(T)=3.47 min, [M+H]⁺=531. ¹H NMR δ (ppm) (DMSO-d6):8.23 (1H, d, J=8.19 Hz), 8.05 (1H, s), 7.04 (1H, dd, J=8.26, 1.80 Hz),6.88 (1H, d, J=1.76 Hz), 5.82-5.72 (1H, m), 4.30 (2H, t, J=5.02 Hz),3.37 (2H, t, J=5.04 Hz), 3.19 (2H, t, J=7.23 Hz), 2.95 (2H, d, J=10.97Hz), 2.75 (6H, s), 2.65 (2H, t, J=7.25 Hz), 2.04 (2H, t, J=11.43 Hz),1.75 (2H, d, J=12.62 Hz), 1.67-1.53 (2H, m), 1.50 (6H, d, J=6.58 Hz). 1Hobscured by solvent

Example 5008-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid dimethylamide 500

Following the procedure for 103,8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (50.0 mg, 0.2 mmol) was reacted with dimethylamine (1.2 equiv) togive 500 (11.7 mg, M+1 341.0)

Example 501{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-2-oxo-2H-pyridin-1-yl}-aceticacid 501

Following the procedure for 477, compound 330 and methyl 2-bromoacetategave the methyl ester of 501 (0.734 mg, 62%). ¹H NMR (500 MHz, DMSO) δ9.17 (d, J=2.4, 1H), 8.09 (s, 1H), 7.78 (dd, J=7.1, 2.0, 1H), 7.73 (dd,J=6.7, 1.9, 1H), 7.59 (dd, J=8.4, 2.4, 1H), 7.08 (d, J=8.4, 1H), 6.42(t, J=6.9, 1H), 5.97 (dt, J=13.4, 6.7, 1H), 4.79 (s, 2H), 4.40 (t,J=4.9, 2H), 3.71 (s, 3H), 3.46 (t, J=4.9, 2H), 1.53 (d, J=6.6, 6H). MS(ESI(+)): m/z 478.2 (M+H)

To the methyl ester of 501 (0.100 g, 0.209 mmol) in acetonitrile (2 mL),THF (2 mL), and water (2 mL) was added lithium hydroxide monohydrate(0.043 g, 1.05 mmol). The mixture was stirred at room temperature for 24hours before concentrating under reduced pressure. EtOAc was added tothe residue that was then washed with 1N HCl. The aqueous layer wasextracted with additional EtOAc and the combined organic layers werewashed with brine, dried over MgSO₄, and concentrated under reducedpressure to provide 501 (0.77 g, 79%). ¹H NMR (500 MHz, DMSO) δ 12.95(s, 1H), 9.16 (s, 1H), 8.09 (s, 1H), 7.73 (dd, J=17.8, 7.0, 2H), 7.60(d, J=8.3, 1H), 7.08 (d, J=8.4, 1H), 6.38 (t, J=6.9, 1H), 6.01-5.93 (m,1H), 4.69 (s, 2H), 4.40 (s, 2H), 3.46 (s, 2H), 1.54 (d, J=6.5, 6H). MS(ESI(+)): m/z 464.2 (M+H)

Example 5023-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1-methyl-1H-pyridin-2-one502

Following the procedure for 477, compound 330 and iodomethane werereacted to give 502 (0.039 g, 20%). ¹H NMR (500 MHz, DMSO) δ 9.05 (d,J=2.3, 1H), 8.09 (s, 1H), 7.73 (dd, J=6.7, 1.9, 1H), 7.66 (ddd, J=10.7,7.7, 2.1, 2H), 7.07 (d, J=8.4, 1H), 6.34 (t, J=6.8, 1H), 5.94 (dt,J=13.2, 6.6, 1H), 4.40 (t, J=4.9, 2H), 3.53 (s, 3H), 3.46 (t, J=5.0,2H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.2 (M+H).

Example 5032-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-2-oxo-2H-pyridin-1-yl}-N,N-dimethyl-acetamide503

Following the procedure for 504, to 501 in THF was addeddiisopropylethylamine, 2M dimethylamine in MeOH, and HATU to give 503(0.030 g, 19%). ¹H NMR (500 MHz, DMSO) δ 9.14 (d, J=2.3, 1H), 8.08 (s,1H), 7.72 (dd, J=7.0, 2.0, 1H), 7.63-7.55 (m, 2H), 7.07 (d, J=8.4, 1H),6.36 (t, J=6.9, 1H), 5.96 (dd, J=13.1, 6.7, 1H), 4.87 (s, 2H), 4.40 (t,J=4.9, 2H), 3.45 (t, J=5.0, 2H), 3.10 (s, 3H), 2.89 (s, 3H), 1.52 (d,J=6.6, 6H). MS (ESI(+)): m/z 491.1 (M+H)

Example 5042-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-2-oxo-2H-pyridin-1-yl}-acetamide504

To 501 (0.150 g, 0.324 mmol) in THF (4 mL) was addeddiisopropylethylamine (0.33 mL, 1.94 mmol), ammonium chloride (0.069 g,1.29 mmol), and HATU (0.184 g, 0.485 mmol). The resulting mixture wasstirred 24 h at room temperature. The reaction mixture was diluted withEtOAc. The solution was washed sequentially with saturated sodiumbicarbonate, water, and brine, before drying over MgSO₄ andconcentrating under reduced pressure to 50 mL of EtOAc. The solids werecollected by filtration to give 504 (0.101 g, 68%). ¹H NMR (500 MHz,DMSO) δ 9.10 (d, J=2.3, 1H), 8.08 (s, 1H), 7.70 (dd, J=7.0, 1.9, 1H),7.61 (ddd, J=10.8, 7.6, 2.1, 2H), 7.07 (d, J=8.4, 1H), 6.34 (t, J=6.9,1H), 5.94 (dt, J=13.1, 6.6, 1H), 4.60 (s, 2H), 4.40 (t, J=4.9, 2H), 3.45(t, J=4.9, 2H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 463.1 (M+H)

Example 5054-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H-pyridin-2-one505 Step 1:9-(2-fluoro-pyridin-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Following the procedure for 128,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6, and fluoropyridin-4-ylboronic acid were reacted to give9-(2-fluoro-pyridin-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(230 mg, 20%). ¹H NMR (500 MHz, DMSO) δ 8.84 (d, J=2.5, 1H), 8.34 (d,J=5.3, 1H), 8.12 (s, 1H), 7.82 (dd, J=8.4, 2.5, 1H), 7.67 (d, J=5.3,1H), 7.48 (s, 1H), 7.24 (d, J=8.4, 1H), 5.82 (dt, J=13.2, 6.6, 1H), 4.45(t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 1.59 (d, J=6.6, 6H). MS (ESI(+)):m/z 408.1 (M+H)

Step 2

Following the procedure for 330,9-(2-fluoro-pyridin-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand HCl were reacted to give 505 (64 mg, 31%). ¹H NMR (500 MHz, DMSO) δ11.57 (s, 1H), 8.73 (d, J=2.4, 1H), 8.11 (s, 1H), 7.66 (dd, J=8.4, 2.4,1H), 7.49 (d, J=7.1, 1H), 7.17 (d, J=8.4, 1H), 6.58 (s, 1H), 6.50 (d,J=5.8, 1H), 5.81 (dt, J=13.2, 6.6, 1H), 4.43 (t, J=4.8, 2H), 3.48 (t,J=4.9, 2H), 1.59 (d, J=6.6, 6H). MS (ESI(+)): m/z 406.1 (M+H)

Example 5065-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H-pyrimidine-2,4-dione506

9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 6 (500 mg, 1.3 mmol) and potassium acetate (380 mg, 3.8mmol) were suspended in N,N-dimethylformamide (5 mL) and water (5 mL)and degassed by bubbling N₂ for 5 min. Charged with2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylboronic acid (250 mg, 1.6mmol) and then tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13mmol). The reaction was microwaved at 300 watts, 140° C. for 20 minutes.Subsequently after cooling to r.t. and diluting with water (20 mL), themixture was extracted with ethyl acetate. The combined organics portionswere concentrated and purified by reverse phase HPLC to provide 506 as awhite crystalline compound (70 mg, 10% yield). LC/MS (ESI+): m/z 423.1(M+H). ¹H NMR (500 MHz, DMSO) δ 1.22 (s, 2H), 8.71 (s, 1H), 8.11 (s,1H), 7.65 (s, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H),5.92-5.81 (m, 1H), 4.38 (s, 2H), 3.45 (s, 2H), 1.55 (d, J=6.5 Hz, 4H)

Example 5072-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-2-oxo-2H-pyridin-1-yl}-N-methyl-acetamide507

Following the procedure for 504, to 501 in THF was addeddiisopropylethylamine, 2M methylamine in MeOH, and HATU to give 507(0.014 g, 9%). ¹H NMR (500 MHz, DMSO) δ 9.11 (d, J=2.3, 1H), 8.08 (s,1H), 7.71 (dd, J=7.0, 2.0, 1H), 7.64 (dd, J=6.7, 1.9, 1H), 7.58 (dd,J=8.4, 2.3, 1H), 7.07 (d, J=8.4, 1H), 6.35 (t, J=6.9, 1H), 5.94 (dt,J=13.0, 6.5, 1H), 4.60 (s, 2H), 4.40 (t, J=4.9, 2H), 3.45 (t, J=4.9,2H), 2.65 (d, J=4.6, 3H), 1.53 (d, J=6.6, 6H). MS (ESI(+)): m/z 477.2(M+H)

Example 5082-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-N-methyl-acetamide508

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene375 TFA salt (300 mg, 0.59 mmol) in THF (5 mL) was added potassiumcarbonate (285 mg, 2.10 mmol) followed by 2-bromo-N-methylacetamide (99mg, 0.65 mmol). The reaction mixture was stirred for 3 hours beforebeing diluted with DCM and water. The organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingresidue was triturated with diethyl ether to give 508 as a brown solid(226 mg, 82%). LCMS: R_(T)=3.21 min, [M+H]⁺=467. ¹H NMR δ (ppm)(DMSO-d₆): 8.28 (1H, d, J=8.19 Hz), 8.10 (1H, s), 7.75-7.68 (1H, m),7.10 (1H, dd, J=8.24, 1.81 Hz), 6.96 (1H, d, J=1.76 Hz), 5.86-5.77 (1H,m), 4.36 (2H, t, J=5.02 Hz), 3.42 (2H, t, J=5.03 Hz), 2.91-2.87 (4H, m),2.64 (3H, d, J=4.74 Hz), 2.55-2.45 (1H, m), 2.19-2.17 (2H, m), 1.76-1.75(4H, m), 1.55 (6H, d, J=6.59 Hz)

Example 5092-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-N,N-dimethyl-acetamide509

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene375 TFA salt (386 mg, 0.76 mmol) in THF (5 mL) was added potassiumcarbonate (210 mg, 1.52 mmol) followed by 2-chloro-N,N-dimethylacetamide(102 mg, 0.84 mmol). The reaction mixture was stirred for 65 hoursbefore being diluted with DCM and water. The organic layer was driedover anhydrous magnesium sulfate and concentrated in vacuo. Theresulting residue was purified by silica gel flash chromatography (SiO₂,gradient 0-3% methanol in DCM) then freeze-dried from methanol and waterto give 509 as a white solid (158 mg, 43%). LCMS: R_(T)=3.33 min,[M+H]⁺=481. ¹H NMR δ (ppm) (DMSO-d₆): 8.27 (1H, d, J=8.20 Hz), 8.09 (1H,d, J=0.59 Hz), 7.09 (1H, dd, J=8.25, 1.83 Hz), 6.93 (1H, d, J=1.77 Hz),5.83-5.81 (1H, m), 4.35 (2H, t, J=5.02 Hz), 3.41 (2H, t, J=5.05 Hz),3.15 (2H, s), 3.05 (3H, s), 2.93 (2H, d, J=10.95 Hz), 2.82 (3H, s),2.48-2.44 (1H, m), 2.16-2.13 (2H, m), 1.81-1.70 (2H, m), 1.66-1.64 (2H,m), 1.54 (6H, d, J=6.59 Hz)

Example 510N-tert-Butyl-2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-acetamide510

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene375 TFA salt (250 mg, 0.49 mmol) in THF (5 mL) was added potassiumcarbonate (136 mg, 0.98 mmol) followed by N-tert-butyl-2-chloroacetamide(81 mg, 0.54 mmol). The reaction mixture was stirred for 65 hours beforebeing diluted with DCM and water. The organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingresidue was purified by silica gel flash chromatography (SiO₂, gradient0-3% methanol in DCM) then freeze-dried from methanol and water to give510 as a beige solid (158 mg, 63%). LCMS: R_(T)=3.67 min, [M+H]⁺=509. ¹HNMR δ (ppm) (CDCl₃): 8.34 (1H, d, J=8.18 Hz), 7.93 (1H, s), 7.10-7.06(2H, m), 6.96 (1H, d, J=1.81 Hz), 5.92-5.91 (1H, m), 4.42 (2H, t, J=5.03Hz), 3.42 (2H, t, J=5.05 Hz), 3.00-2.91 (4H, m), 2.61-2.48 (1H, m),2.35-2.24 (2H, m), 1.96-1.87 (3H, m), 1.83-1.71 (1H, m), 1.64 (6H, d,J=6.63 Hz), 1.39 (9H, s)

Example 5112-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methoxy-ethyl)-piperidin-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene511

A mixture of8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 (2.00 g, 5.11 mmol), bis(neopentylglycolato)diboron (1.73 g, 7.67mmol) and potassium acetate (1.76 g, 17.89 mmol) in 1,4-dioxan (20 mL)was stirred while nitrogen was bubbled through for 10 min beforeaddition PdCl₂dppf.DCM (0.209 g, 0.256 mmol). The reaction mixture washeated at 90° C. for 6.5 h before the cooled mixture was diluted withDCM (200 mL) and stirred for 15 min with activated charcoal. The mixturewas filtered and the filtrate was concentrated in vacuo. The resultantresidue was sonicated with cyclohexane and the solid was filtered offand dried (vacuum, 40° C.) to give8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(1.97 g, 91%). LCMS R_(T)=3.78, [M+H]⁺=357 (hydrolysis product). ¹H NMR400 MHz (CDCl₃) δ: 8.36 (1H, d, J=7.87 Hz), 7.92 (1H, s), 7.60 (1H, dd,J=7.86, 1.25 Hz), 7.51 (1H, d, J=1.20 Hz), 5.93 (1H, t, J=6.62 Hz), 4.40(2H, t, J=5.10 Hz), 3.79 (4H, s), 3.43 (2H, t, J=5.12 Hz), 1.63 (6H, d,J=6.63 Hz), 1.04 (6H, s).

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene375 (300 mg, 0.59 mmol) in DMF (3.5 mL) was added 2-bromoethyl methylether (60 μl, 0.65 mmol) and potassium carbonate (285 mg, 2.07 mmol) andthe reaction mixture stirred at 60° C. for 2 h. The reaction mixture wasdiluted with DCM and washed with saturated aqueous sodium bicarbonate,then water followed by brine, dried (MgSO₄) and concentrated in vacuo.The resultant residue was subjected to flash chromatography (SiO₂,gradient 0-10% MeOH in DCM) followed by trituration in cyclohexane togive 511 (187 mg, 70%). LCMS: R_(T)=3.42 min, [M+H]⁺=454. ¹H NMR 400 MHz(DMSO-d6) δ: 8.23 (1H, d, J=8.19 Hz), 8.05 (1H, s), 7.04 (1H, dd,J=8.22, 1.79 Hz), 6.88 (1H, d, J=1.74 Hz), 5.77-5.76 (1H, m), 4.31 (2H,t, J=5.00 Hz), 3.44-3.34 (5H, m), 3.20 (3H, s), 2.93 (3H, d, J=10.98Hz), 2.02 (2H, t, J=11.43 Hz), 1.71 (3H, m), 1.64-1.53 (2H, m), 1.50(6H, d, J=6.58 Hz)

Example 5122-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-ethanol512 Step 1:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene375 (310 mg, 0.61 mmol) in DMF (3.5 mL) was added2(2-bromoethoxy)tetrahydro-2H-pyran (0.1 mL, 0.67 mmol) and potassiumcarbonate (290 mg, 2.10 mmol) and the reaction mixture stirred at 60° C.for 16 h. The reaction mixture was diluted with DCM and washed withsodium bicarbonate (sat aq.) then water followed by brine, dried (MgSO₄)and concentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO₂, gradient 0-10% MeOH in DCM) to give2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(106 mg, 33%). LCMS: R_(T)=3.71 min, [M+H]⁺=524 ¹H NMR 400 MHz (DMSO-d6)δ: 8.27 (1H, d, J=8.19 Hz), 8.09 (1H, d, J=0.58 Hz), 7.09 (1H, dd,J=8.26, 1.82 Hz), 6.92 (1H, d, J=1.78 Hz), 5.82-5.82 (1H, m), 4.58 (1H,t, J=3.52 Hz), 4.35 (2H, t, J=5.02 Hz), 3.75-3.74 (2H, m), 3.44-3.42(4H, m), 2.99 (2H, t, J=10.97 Hz), 2.54 (2H, t, J=6.17 Hz), 2.47 (1H,s), 2.09 (2H, t, J=11.61 Hz), 1.79-1.55 (6H, m), 1.55 (6H, d, J=6.59Hz), 1.52-1.43 (4H, m).

Step 2

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(103 mg, 0.20 mmol) in MeOH (2 mL) was added HCl (1 mL, 4N in dioxan)and the reaction mixture stirred at RT for 30 min. The reaction mixturewas concentrated in vacuo and the residue freeze dried from MeOH/H₂O togive 512 as a solid (136 mg). LCMS: R_(T)=3.16 min, [M+H]⁺=440[ad823338] ¹H NMR 400 MHz (d₆-DMSO) δ: 8.27 (1H, d, J=8.19 Hz), 8.03(1H, s), 7.04 (1H, dd, J=8.13, 1.84 Hz), 6.89 (1H, d, J=1.75 Hz),5.79-5.71 (1H, m), 4.31 (2H, t, J=5.0 Hz), 3.74 (2H, t, J=5.0 Hz), 3.57(2H, d, J=12.01 Hz), 3.37 (2H, t, J=4.96 Hz), 3.08-3.07 (4H, m), 2.79(1H, t, J=7.80 Hz), 1.98-1.97 (4H, m), 1.49 (6H, d, J=6.59 Hz)

Example 5132-(2-Isopropyl-2H-5-amino[1,2,4]triazol-3-yl)-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene513

Following the procedures of Example 516,1-(5-fluoro-2-hydroxyphenyl)ethanone was converted to 513.

Example 5141-(8-Piperidin-4-yl-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione514 Step 1: tert-Butyl4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dionewas coupled with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylateto give tert-butyl4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate.Yield 19%. MS(ESI+):511.3

Step 2: tert-Butyl4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-tetrahydropyridine-1(2H)-carboxylate

Tert-butyl4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate(48 mg, 0.094 mmol) in 6 ml of ethanol was hydrogenated at 1 atm over 50mg of 10% palladium on charcoal for 18 hours. The mixture was filteredthrough celite and concentrated in vacuum giving 49 mg (100%) oftert-butyl4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-tetrahydropyridine-1(2H)-carboxylate.MS(ESI+): 513.3

Step 3

tert-Butyl4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-tetrahydropyridine-1(2H)-carboxylatewas stirred in 50% trifluoroacetic acid in dichloromethane to give 514.Yield 30%. MS(ESI+):413.2. 1H NMR (500 MHz, DMSO) δ 8.23 (s, 1H), 8.17(d, J=8.2, 1H), 7.02 (d, J=8.2, 1H), 6.85 (d, J=1.6, 1H), 4.30 (t,J=4.9, 2H), 3.22-3.20 (m, 3H), 2.88 (t, J=11.2, 2H), 2.75 (t, J=12.0,1H), 1.89 (d, J=12.5, 2H), 1.67 (d, J=12.9, 7H)

Example 5155-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H—N-methylpyridin-2-one515

Following the procedure for 477, to 496 in DMF was added iodomethane andcesium fluoride to give 515 (0.014 g, 7%). ¹H NMR (500 MHz, DMSO) δ 8.52(d, J=2.4, 1H), 8.11 (s, 1H), 8.08 (d, J=2.6, 1H), 7.78 (dd, J=9.5, 2.7,1H), 7.50 (dd, J=8.4, 2.4, 1H), 7.14 (d, J=8.4, 1H), 6.53 (d, J=9.4,1H), 5.80 (dt, J=13.2, 6.5, 1H), 4.40 (t, J=5.0, 2H), 3.52 (s, 3H), 3.47(t, J=5.0, 2H), 1.58 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)

Example 5162-(2-Isopropyl-2H-5-amino[1,2,4]triazol-3-yl)-9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene516 Step 1: 1-(2-(2-bromoethoxy)-5-fluorophenyl)ethanone

Dissolved 1-(5-fluoro-2-hydroxyphenyl)ethanone (10.0 g, 64.9 mmol) in 18mL 1,2-Dibromoethane and added Potassium carbonate (18.8 g, 136 mmol)and 100 mL 2-Butanone. Heated the reaction mixture to reflux and allowedto stir overnight under nitrogen. Reaction was complete by LCMS. Dilutedreaction mixture with water and extracted the product with ethylacetate. Concentrated in vacuo and purified by flash chromatography (0to 30% ethyl acetate/heptanes) to give 3.71 g (21.9% yield) of1-(2-(2-bromoethoxy)-5-fluorophenyl)ethanone.

Step 2: 7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one

Weighed out Sodium Hydride (561 mg, 23.4 mmol) into a nitrogen purgedround bottom flask and added 10 mL THF. Placed the solution undernitrogen and added 1-(2-(2-bromoethoxy)-5-fluorophenyl)ethanone (4.07 g,15.6 mmol) in 15 mL THF. Let stir at room temperature overnight.Concentrated in vacuo and flashed 0 to 50% ethyl acetate/hexanes. NMRconfirmed product as 7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.58g, 56.2% yield).

Step 3: 4-bromo-7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one

Dissolved 7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.58 g, 8.77mmol) in 80 mL ether and added bromine (0.497 mL, 9.65 mmol) and allowedthe reaction mixture to stir at room temperature 20 hours. Reaction wascomplete by LCMS. Concentrated the reaction in vacuo and purified byflash chromatography (0 to 30% ethyl acetate/heptanes). Concentrated invacuo and NMR indicated4-bromo-7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one.

Step 4:9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid ethyl ester

Dissolved 4-bromo-7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.06 g,4.09 mmol) in ethanol (100 mL) and added Ethyl Thioamidooxalate (1.09 g,8.18 mmol). Heated to reflux with a vigreux condensation columnattached. Allowed to stir a reflux overnight and confirmed completereaction by LCMS. Concentrated in vacuo and purified by flashchromatography using ethyl acetate/heptanes (0 to 10% over 60 minutes)to give 0.75 g (62% yield) of9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid ethyl ester

Step 5:9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid

Dissolved9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid ethyl ester (0.75 g, 2.6 mmol) in 30 mL THF and added 1 M LithiumHydroxide (10 mL, 10 mmol). Allowed reaction mixture to stir for 2 hoursat room temperature. Reaction was complete by LCMS. THF was removed byrotovap and the aqueous layer was acidified with 1 M HCl. The productwas extracted by DCM and concentrated in vacuo to give 0.68 g (100%yield unpurified) of9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid.

Step 5: tert-butyl amino(methylthio)methylenecarbamate

2-Methyl-2-thiopseudourea sulfate (20.0 g, 71.8 mmol) was dissolved inmethylene chloride (100 mL) and sodium hydroxide (9.22 g, 0.230 mol) in110 mL of water was added. The solution was cooled to −10° C. in an iceand brine bath. Di-tert-Butyldicarbonate (11.6 g, 53.2 mmol) was addedin 40 mL of DCM dropwise over 2 hours by syringe pump. The solution wasallowed to warm up to room temperature and stir over the week-end. Thesolution was diluted with water and extracted with methylene chloride,washed with brine and concentrated in vacuo to give 13.7 g (68.9% yield)of tert-butyl amino(methylthio)methylenecarbamate

Step 6:9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid

Suspended9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylicacid (0.68 g, 2.6 mmol) in 30 mL methylene chloride and 30 mLacetonitrile and added oxalyl chloride (0.434 mL, 5.13 mmol) andN,N-Dimethylformamide (19.8 uL, 0.256 mmol) and let the reaction mixturestir for 30 minutes. Complete formation of the acid chloride wasconfirmed by TLC after quenching an aliquot with triethylamine. Reactionwas concentrated in vacuo and dissolved in methylene chloride again (20mL). tert-Butyl amino(methylthio)methylenecarbamate was added (536 mg,2.82 mmol) followed by triethylamine (0.52 ml, 3.7 mmol). The reactionwas heated to 90° C. and allowed to stir for 3.5 hours. Reaction wascomplete by TLC and was diluted with water and the product extractedwith methylene chloride, concentrated in vacuo, and purified by flashchromatography using ethyl acetate/hexanes (0 to 40%) and concentratedin vacuo to give 0.69 g (62% yield) of the tert-butyl carbamateintermediate

Step 7

The tert-butyl carbamate intermediate from Step 6 (0.69 g, 1.6 mmol) wasdissolved in 30 mL N,N-dimethylformamide (DMF). Isopropyl hydrazinehydrochloride (0.52 g, 4.7 mmol) followed by N,N-Diisopropylethylamine(1.65 mL, 9.46 mmol) were added and let stir at 70° for 3.5 hours.Complete reaction was confirmed by LCMS and the reaction mixture wasconcentrated in vacuo and purified by flash chromatography in ethylacetate/heptanes (0 to 40%) to give the tert-butyloxycarbonylintermediate which was immediately dissolved in 1,2-dichloroethane and1.5 mL (19 mmol) of trifluoroacetic acid was added. The reaction mixturewas heated to 40° C. for 4.5 hours and complete deprotection wasconfirmed by LCMS. Reaction was concentrated in vacuo and the finalproduct purified by HPLC to give 220 mg (40% yield) of 516.

Example 5174-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-4-olhydrochloride 517

8-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(200 mg, 0.47 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester(63 mg, 0.31 mmol), bis(1,5-cyclooctadiene)nickel(0) (17 mg, 0.063mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (27 mg, 0.063mmol) and cesium fluoride (81 mg, 0.53 mmol) were loaded into a reactionvial, which was then flushed with nitrogen. Dry toluene (3 mL) was thenadded and nitrogen was bubbled through the mixture for 15 min. beforeheating at 80° C. for 30 min. The reaction mixture was combined with amixture from a similar reaction (same quantities of boronate ester andoxo-piperidine, half-quantities of nickel and imidazolium catalysts,heated for 19.5 h) and extracted with ethyl acetate. The organic extractwas washed with saturated aqueous sodium bicarbonate followed by brine,then dried (Na₂SO₄) and concentrated in vacuo. The resultant residue wassubjected to flash chromatography (SiO₂, gradient 20-70% ethyl acetatein cyclohexane) to give4-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (100 mg). LCMS R_(T)=4.73, [M+H]⁺=512.

To a solution of4-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (20 mg, 39 μmol) in DCM (2 mL) was added TFA (0.5mL) and the reaction mixture stirred at RT for 3 h. The reaction mixturewas concentrated in vacuo and the resultant residue subjected to flashchromatography (Si—NH₂, gradient 1-4% MeOH in DCM). The purified productwas dissolved in MeOH (5 mL) and HCl (0.5 mL, 3N in MeOH) added. Thereaction mixture was concentrated in vacuo and the residue trituratedwith MeCN to give 517 as a colourless solid (9 mg, 51%). LCMS:R_(T)=2.94 min, [M+H]⁺=412 [ad823591] ¹H NMR 400 MHz (d₆-DMSO) δ: 8.38(1H, d, J=8.2 Hz), 7.97 (1H, s), 7.28 (1H, dd, J=8.2, 1.9 Hz), 7.20 (1H,d, J=1.9 Hz), 5.93 (1H, sept, J=6.6 Hz), 4.37 (2H, t, J=5.0 Hz),3.49-3.29 (6H, m), 2.29-2.17 (2H, m), 1.98-1.90 (2H, m), 1.59 (6H, d,J=6.6 Hz)

Example 5182-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methoxy-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene518

To a solution of8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,from Example 519, (0.300 g, 0.786 mmol) and Cesium Carbonate (0.384 g,0.00118 mol) in N,N-Dimethylformamide (7.9 mL) was added1-bromo-2-methoxyethane, (0.0739 mL, 0.786 mmol) dropwise. The reactionwas stirred at room temperature overnight. The mixture was diluted withwater and methylene chloride and extracted 3 times with methylenechloride. The crude was purified by column chromatography followed byreverse-phase HPLC to obtain 518 as a white solid (66.3 mg). MS(ESI+)440.2. ¹H NMR (400 MHz, DMSO) δ 8.28 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2,1.5 Hz, 1H), 7.02 (d, J=1.5 Hz, 1H), 5.76 (hept, J=6.6 Hz, 1H),4.38-4.32 (m, 2H), 3.66-3.52 (m, 3H), 3.41 (t, J=5.0 Hz, 2H), 3.34-3.29(m, 2H), 3.23 (s, 3H), 3.15-3.07 (m, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.32(s, 3H), 1.52 (d, J=6.6 Hz, 6H)

Example 5192-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanol519

To a solution of8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidamide (9.040 g, 0.02780 mol) in Toluene (150 mL) was addeddimethylacetamide-dimethylacetal (12.38 mL, 0.08340 mol). The reactionwas stirred at 95° C. for 4 hours. The toluene was then removed in vacuoand the crude was carried forward without further purification. Thecrude material was redissolved in acetic acid (90 mL).Isopropylhydrazine hydrochloride (3.689 g, 0.03336 mol) was added andthe reaction was stirred at room temperature overnight. The acetic acidwas then removed in vacuo. The crude material was triturated inisopropyl alcohol, and filtered to give8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneas a light yellow solid (10.422 g). MS(ESI+) 405.0/407.0

Zinc (2.472 g, 0.03780 mol) was stirred in 10 mL of degassedN,N-dimethylacetamide under N₂ atmosphere. Chlorotrimethylsilane (0.411mL, 0.00324 mol) and 1,2-Dibromoethane (0.233 mL, 0.00270 mol) wereadded and the mixture was stirred for 20 minutes. Tert-butyl3-iodoazetidine-1-carboxylate (7.644 g, 0.02700 mol) in degassedN,N-dimethylacetamide (60.0 mL) was added slowly and the cloudy reactionwas stirred at room temperature for 1.5 hours to give(1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide.

8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(5.000 g, 0.01234 mol) was dissolved in N,N-dimethylacetamide (35 mL)and the solution was degassed for 5 minutes.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.5037 g, 0.0006168 mol) and copper(I)iodide (0.2349 g, 0.001234 mol) were added and the reaction was furtherpurged with N₂. (1-(Tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide(0.01480 mol, 0.38M in DMA, 40 mL), was added and the reaction washeated to 80° C. overnight. Saturated NH₄Cl and methylene chloride wereadded. The mixture was extracted 3 times with methylene chloride. Theorganic phases were combined, dried with MgSO₄ and concentrated. Thecrude was purified by flash chromatography (10-80% ethyl acetate inhexanes) to afford3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester as a white solid (4.11 g). MS(ESI+) 482.2

To a solution of3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylicacid tert-butyl ester (4.11 g, 0.01234 mol) in methylene chloride (42mL) was added trifluoroacetic acid (20 mL) dropwise. The reaction wasstirred at room temperature for 1 hour. Water and ethyl acetate wereadded and the mixture was extracted with 1N HCl. The aqueous phase wasbasified to pH 13 with 1N NaOH. The aqueous phase was filtered andrinsed with cold water to afford8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneas an off-white solid (3.2 g). MS(ESI+) 382.2

To a solution of8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.300 g, 0.000786 mol) in methylene chloride (4.33 mL) was added2-(tert-butyldimethylsilyloxy)acetaldehyde (0.449 mL, 0.00236 mol) andacetic acid (2.68 mL, 0.0472 mol) followed by sodiumtriacetoxyborohydride (1.000 g, 0.004718 mol). The reaction was stirredat room temperature for 3 hours. The reaction was quenched with 1N NaOH.Methylene chloride was added and the mixture was extracted 3 times withmethylene chloride. The organic phases were combined, dried with MgSO₄and concentrated. The crude material was redissolved in methanol (6.69mL). Hydrogen chloride (0.000786 mol, 4N in dioxanes, 0.2 mL) was addeddropwise and the reaction was stirred at room temperature for 2 hours.1N NaOH was added until the solution was basic. The mixture wasextracted 3 times with methylene chloride. The organic phases werecombined, dried with MgSO₄ and concentrated. The crude was purified byreverse-phase HPLC to give 519 as a white solid (89.6 mg). m+1 426.2MS(ESI+) 426.2. ¹H NMR (400 MHz, DMSO) δ 8.28 (d, J=8.2 Hz, 1H), 7.19(dd, J=8.2, 1.5 Hz, 1H), 7.03 (d, J=1.4 Hz, 1H), 5.85-5.66 (m, 1H),4.39-4.32 (m, 3H), 3.67-3.53 (m, 3H), 3.41 (t, J=5.1 Hz, 2H), 3.39-3.34(m, 2H), 3.15-3.08 (m, 2H), 2.54-2.50 (m, 2H), 2.32 (s, 3H), 1.52 (d,J=6.6 Hz, 6H)

Example 5201-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-3-methoxy-propan-2-ol520

To a solution of8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,from Example 519, (0.300 g, 0.000786 mol) and cesium carbonate (0.384 g,0.00118 mol) in N,N-dimethylformamide (7.9 mL) was added1-chloro-3-methoxy-2-propanol (0.0844 mL, 0.786 mmol) dropwise. Thereaction was heated to 50° C. overnight. Sodium iodide (0.236 g, 0.00157mol) was added and stirring was continued at 50° C. The mixture wasdiluted with water and methylene chloride and extracted 3 times withmethylene chloride. Purify by flash chromatography then reverse-phaseHPLC to obtain 520 as a white solid (22.5 mg). MS(ESI+) 470.2

Example 5218-[1-(2-Fluoro-ethyl)-azetidin-3-yl]-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene521

To a solution of8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,from Example 519, (0.300 g, 0.000786 mol) and cesium carbonate (0.384 g,0.00118 mol) in N,N-dimethylformamide (7.9 mL) was added2-fluoro-1-iodoethane (0.137 g, 0.000786 mol) dropwise. The reaction wasstirred at room temperature overnight. The mixture was diluted withwater and methylene chloride and extracted 3 times with methylenechloride. The crude was purified by column chromatography thenreverse-phase HPLC to obtain 521 as a white solid (84.0 mg). m+1 428.1MS(ESI+) 428.1. ¹H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2 Hz, 1H), 7.20(dd, J=8.2, 1.3 Hz, 1H), 7.04 (d, J=1.1 Hz, 1H), 5.84-5.66 (m, 1H), 4.48(t, J=4.9 Hz, 1H), 4.40-4.32 (m, 3H), 3.70-3.56 (m, 3H), 3.42 (t, J=5.0Hz, 2H), 3.20-3.14 (m, 2H), 2.73 (dt, J=28.8, 4.9 Hz, 2H), 2.32 (s, 3H),1.52 (d, J=6.6 Hz, 6H)

Example 5222-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-phenyl}-acetamide522

A solution of crude{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-phenyl}-aceticacid (0.38 mmol) in 5 mL DMF was treated sequentially with DIPEA (0.33mL, 1.92 mmol), ammonium chloride (164 mg, 3.1 mmol) and HATU (292 mg,0.77 mmol). The reaction was monitored by LCMS. After completeconversion, the mixture was diluted with water and extracted withethylacetate. The combined organics were washed with brine, dried oversodium sulfate and concentrated. The crude residue was purified byreverse phase HPLC to give 522 as a colorless solid (93 mg, 56%). LCMS:446.1. ¹H NMR (400 MHz, DMSO) δ 8.45 (d, J=8.3 Hz, 1H), 8.11 (s, 1H),7.66 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.54 (dd, J=8.3, 1.8 Hz, 1H), 7.49(s, 1H), 7.44-7.35 (m, 2H), 7.27 (d, J=7.6 Hz, 1H), 6.88 (s, 1H),5.92-5.78 (m, 1H), 4.43 (t, J=4.9 Hz, 2H), 3.47 (overlapping m, 4H),1.57 (d, J=6.6 Hz, 6H)

Example 5232-{4-Fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-N,N-dimethyl-acetamide523

To a solution of4-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester, from Example 511, (80 mg, 0.16 mmol) in DCM (8mL) at −78° C. was added DAST (200 μL, 1.52 mmol). The reaction mixturewas stirred at −78° C. for 30 min then allowed to warm to RT and stirredfor 16 h. The reaction mixture was stirred at RT for 16 h then dilutedwith DCM (20 mL) and washed with saturated aqueous sodium bicarbonatesolution. The aqueous layer was extracted with DCM (3×5 mL) and thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo. The resultant residue was subjected to flash chromatography(SiO₂, 20% ethyl acetate in DCM) to give4-Fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (45 mg, 56%). LCMS: R_(T)=5.05 min, [M+H]⁺=514

To a solution of4-fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (45 mg, 88 μmol) in DCM (2.5 mL) was added TFA(0.8 mL) and the reaction mixture stirred at RT for 1 h before beingconcentrated in vacuo. The residue was dissolved in DCM (2 mL) andtriethylamine (88 μL, 0.61 mmol), tetrabutylammonimum iodide (8 mg, 21μmol) and 2-chloro-N,N-dimethyl-acetamide (14 μL, 0.1 mmol) added. Thereaction mixture was stirred at RT for 16 h then diluted with DCM (20mL) and washed with saturated aqueous sodium bicarbonate solution. Theaqueous layer was extracted with DCM (3×5 mL) and the combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (SiO₂ 20% ethylacetate in DCM then 2% MeOH in DCM) producing impure material. Thematerial was subjected to flash chromatography (Si—NH₂ eluting with DCM)to yield 523. LCMS: R_(T)=3.43 min, [M+H]⁺=499 [ad823805] ¹H NMR 400 MHz(d₆-DMSO) δ: 8.37 (1H, d, J=8.4 Hz), 7.96 (1H, s), 7.18 (1H, dd, J=1.8,8.4 Hz), 7.09 (1H, d, J=1.8 Hz), 5.93 (1H, sept, J=6.6 Hz), 4.37 (2H, t,J=5.1 Hz), 3.42 (2H, t, J=5.1 Hz), 3.30 (2H, s), 3.09 (3H, s), 2.93 (3H,s), 2.92-2.85 (2H, m), 2.55-2.46 (2H, m), 2.31-2.11 (2H, m), 1.97-1.87(2H, m), 1.59 (6H, d, J=6.6 Hz)

Example 524{1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methyl}-urea524

Following the procedures for 542,C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine532 was reacted with potassium cyanate in acetic acid and water to give524. MS(ESI+) 399.1. ¹H NMR (400 MHz, DMSO) δ 8.27 (d, J=8.2 Hz, 1H),7.07 (dd, J=8.2, 1.3 Hz, 1H), 6.95 (br, 1H), 6.44 (t, J=6.1 Hz, 1H),5.83-5.68 (m, 1H), 5.54 (s, 2H), 4.35 (t, J=5.0 Hz, 2H), 4.18 (d, J=6.1Hz, 2H), 3.42 (t, J=5.0 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H).

Example 5251-ethyl-3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-urea525

To a solution ofC-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine532 (0.050 g, 0.00014 mol) in tetrahydrofuran (1.0 mL) was addedtriethylamine (0.0588 mL, 0.000422 mol) then isocyanatoethane (0.110 mL,0.00141 mol). The reaction was stirred at room temperature overnight,quenched with a small amount of methanol and concentrated in vacuo. Thecrude was precipitated from MeOH/H₂O to give 525. MS(ESI+) 427.1

Example 5263-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-ol526

Following the procedures for 519,8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with 3-(tert-butyldimethylsilyloxy)propanal to give 526.MS(ESI+) 440.2

Example 527N-Isopropyl-2-{3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide527

2-Chloro-N-isopropylacetamide (0.124 g, 0.917 mmol) andtetra-n-butylammonium iodide (0.678 g, 0.00183 mol) were premixed inmethylene chloride (3 mL). This solution was added dropwise to asolution of8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenefrom Example 519 (0.350 g, 0.917 mmol) and triethylamine (0.256 mL,0.00183 mol) in methylene chloride (7 mL). The reaction was stirred atroom temperature for 24 hours. Water was added and the mixture wasextracted 3 times with methylene chloride. The organic layers werecombined, dried with MgSO₄ and concentrated. The crude was purified byreverse-phase HPLC to obtain 527 as a white solid (51 mg). MS(ESI+)481.2. ¹H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2 Hz, 1H), 7.42 (d, J=7.9Hz, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H), 5.87-5.65(m, 1H), 4.36 (t, J=5.0 Hz, 2H), 3.87 (dq, J=13.2, 6.6 Hz, 1H),3.76-3.59 (m, 3H), 3.42 (t, J=5.0 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.04(s, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H), 1.07 (d, J=6.6 Hz, 6H)

Example 5284-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H—N-methylpyridin-2-one528

Following the procedure for 477, to 505 in DMF was added iodomethane andcesium fluoride to give 528 (0.077 g, 10%). ¹H NMR (400 MHz, DMSO) δ8.74 (d, J=2.4, 1H), 8.12 (s, 1H), 7.82 (d, J=7.1, 1H), 7.68 (dd, J=8.4,2.4, 1H), 7.18 (d, J=8.4, 1H), 6.67 (d, J=1.9, 1H), 6.55 (dd, J=7.1,2.0, 1H), 5.81 (dt, J=13.1, 6.4, 1H), 4.43 (t, J=4.9, 2H), 3.46 (s, 5H),1.59 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)

Example 5292-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-oxetan-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene529

2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with 3-iodooxetane in a CEM microwave vial withnickel(II)iodide, trans-2-aminocyclohexanol hydrochloride and sodiumhexamethyldisilazane to give 529. MS(ESI+) 383.1. ¹H NMR (400 MHz, DMSO)δ 8.34 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.2, 1.4 Hz, 1H), 7.08 (d, J=1.3Hz, 1H), 5.76 (hept, J=6.8 Hz, 1H), 4.94 (dd, J=8.3, 5.9 Hz, 2H), 4.63(t, J=6.3 Hz, 2H), 4.37 (t, J=5.0 Hz, 2H), 4.31-4.20 (m, 1H), 3.43 (t,J=5.0 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)

Example 5304-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-1H-pyridin-2-one530

Following the procedures for 128,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with 2-fluoropyridin-4-ylboronic acid to give2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(2-fluoropyrid-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.60 g, 30%). MS (ESI(+): m/z 408.0 (M+H)

Following the procedures for 330,2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(2-fluoropyrid-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand HCl were reacted to give 530 (0.352 g, 60%). ¹H NMR (400 MHz, DMSO)δ 11.62 (s, 1H), 8.45 (d, J=8.3, 1H), 8.12 (s, 1H), 7.56 (d, J=8.2, 1H),7.45 (d, J=6.8, 1H), 7.40 (s, 1H), 6.64 (s, 1H), 6.57 (d, J=6.8, 1H),5.84 (dt, J=13.1, 6.5, 1H), 4.42 (t, J=4.8, 2H), 3.48 (t, J=4.8, 2H),1.56 (d, J=6.6, 6H). MS (ESI(+)): m/z 406.1 (M+H)

Example 5312-(2-Isopropyl-2H-5-methoxymethyl[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene531

Step 1:N′-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylicacid tert-butyl ester

To a mixture of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid(5.20 g, 16.0 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butylester (3.33 g, 19.1 mmol) in DMF (100 mL) at 0° C. was added DIPEA (6.93mL, 39.9 mmol) followed by HATU (9.09 g, 23.9 mmol). The reactionmixture was stirred at RT for 72 h before being concentrated in vacuo.The resultant residue was treated with water then extracted with DCM(×3) before the combined organic extracts were washed with 10% citricacid, then saturated sodium bicarbonate solution followed by brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo togive a brown oil. The oil was extracted with diethyl ether (×5) and thediethyl ether extracts concentrated in vacuo before being trituratedwith pentane to give the title compound as a light brown solid (6.14 g,12.7 mmol, 80%). LCMS: R_(T)=5.02 min, [M+H]⁺=482/484.

Step 2:8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidN-isopropyl-hydrazide hydrochloride

A suspension ofN′-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylicacid tert-butyl ester (6.14 g, 12.7 mmol) in methanol (49 mL) wastreated with 4N HCl in dioxan (12.7 mL, 51.0 mmol) and stirred at RT for0.75 h before being warmed to 50° C. and stirred for 3 h. The reactionmixture was concentrated in vacuo and the resultant solid was trituratedwith diethyl ether to give the title compound as a yellow brown solid(5.14 g, 12.3 mmol, 96%). LCMS: R_(T)=4.79 min, [M+H]⁺=382/384.

Step 3:8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidN-isopropyl-N′-(2-methoxy-acetyl)-hydrazide

To a mixture of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidN-isopropyl-hydrazide hydrochloride (3.5 g, 8.4 mmol) and TEA (4.07 mL,29.3 mmol) in DCM (35 mL) at 0° C. was added methoxy-acetyl chloride(1.53 mL, 16.7 mmol) dropwise and the reaction mixture was stirred at 0°C. for 0.75 h then 18 h at RT. The reaction was quenched by the additionof saturated aqueous sodium bicarbonate solution and the phasesseparated. The aqueous phase was extracted with DCM (×2) before thecombined organic extracts were washed with 10% citric acid solution,followed by brine then dried (Na₂SO₄) and concentrated in vacuo to givea yellow brown solid. The solid was triturated with diethyl ether togive the title compound as an off white solid (2.66 g, 5.86 mmol, 70%).LCMS R_(T)=4.64 min, [M+H]⁺=454/456.

Step 4:8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

A suspension of8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acidN-isopropyl-N′-(2-methoxy-acetyl)-hydrazide (2.66 g, 5.86 mmol) inphosphorus (V) oxychloride (26 mL) was stirred at 100° C. for 18 h. Thereaction mixture was concentrated in vacuo and the resultant residueazeotroped with toluene (×4) affording a brown solid. The solid wastreated with acetic acid (26 mL) and ammonium acetate (4.51 g, 58.6mmol) before the mixture was stirred at 125° C. for 1 h. A furtheraddition of ammonium acetate (2.31 g, 30.0 mmol) was made and thereaction stirred at 125° C. for 2 h before being concentrated in vacuo.The resultant residue was diluted with water and extracted with DCM (×2)before the combined organic extracts were washed with saturated sodiumbicarbonate solution followed by brine, then dried (Na₂SO₄) andconcentrated in vacuo to give a pale brown solid. The solid was treatedwith phosphorus (V) oxychloride (26 mL) and stirred at 100° C. for 24 hbefore being concentrated in vacuo then treated with acetic acid (23 mL)and ammonium acetate (4.23 g, 55.0 mmol). The mixture was stirred at125° C. for 1.5 h then concentrated in vacuo and azeotroped with toluene(×4). The resultant residue was diluted with water and extracted withDCM (×2) and the combined organic extracts were washed with saturatedsodium bicarbonate solution followed by brine, then dried (Na₂SO₄) andconcentrated in vacuo to give a brown solid. The solid wasrecrystallised from methanol/chloroform to give the title compound as adark brown solid (1.17 g, 2.69 mmol, 46%). LCMS R_(T)=4.97 min,[M+H]⁺=435/437. ¹H NMR 400 MHz (DMSO-d6) δ: 8.23 (1H, d, J=8.58 Hz),7.36 (1H, dd, J=8.58, 2.10 Hz), 7.26 (1H, d, J=2.07 Hz), 5.72-5.71 (1H,m), 4.39 (2H, s), 4.35 (2H, t, J=5.02 Hz), 3.39 (2H, t, J=5.02 Hz), 3.29(3H, s), 1.49 (6H, d, J=6.59 Hz).

Step 5

To a solution of8-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(1.17 g, 2.7 mmol) in IMS (15 mL) and chloroform (10 mL) was added water(3 mL), ammonium formate (1.69 g, 27 mmol) and palladium on carbon (10%by wt, 350 mg). The reaction mixture was heated at 50° C. for 1 hour.Palladium on carbon (10% by wt, 350 mg) was added and heating continuedfor 4.5 h. More palladium on carbon (10% by wt, 350 mg) was added andthe reaction mixture heated at 50° C. for 16 h. The reaction mixture wasfiltered and the solids washed with chloroform. The filtrate was washedwith water extracting with DCM (2×20 mL). The combined organic extractswere washed with citric acid (10% aqueous) then brine, dried (MgSO₄) andconcentrated in vacuo. The resultant residue was subjected to flashchromatography (SiO₂ eluting with 0-50% ethyl acetate in cyclohexane) togive the title compound (456 mg). A portion of this material was furtherpurified by RPHPLC (C18 column, gradient 50-95% MeOH in water, +0.1%formic acid) to give 531. LCMS: R_(T)=5.41 min, [M+H]⁺=357 [ad823933][NMR 72713] ¹H NMR 400 MHz (d₆-DMSO) δ: 8.31 (1H, dd, J=7.9, 1.8 Hz),7.29-7.23 (1H, m), 7.19-7.13 (1H, m), 7.03 (1H, dd, J=7.9, 1.2 Hz), 5.76(1H, sept, J=6.6 Hz), 4.40 (2H, s), 4.32 (2H, t, J=5.0 Hz), 3.40 (2H, t,J=5.0 Hz), 3.30 (3H, s), 1.50 (6H, d, J=6.6 Hz)

Example 532C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine532

To a CEM microwave vial was added8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(1.000 g, 0.002467 mol) and degassed N,N-Dimethylformamide (12.00 mL).The mixture was thoroughly purged with N₂. Zinc cyanide (0.2897 g,0.002467 mol) and tetrakis(triphenylphosphine)palladium(0) (0.1426 g,0.0001234 mol) were added in one portion and the vial was immediatelysealed. The reaction was submitted to microwave irradiation at 60 W for30 minutes (T_(max)=175° C.). The mixture was diluted with methylenechloride and washed with saturated NH₄Cl. The organic layers werecombined, dried with MgSO₄ and concentrated. The crude was loaded as asolid onto silica gel and purified by flash chromatography (10-100%EtOAc in hexanes) to give2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbonitrileas a light yellow solid (593 mg). MS(ESI+) 352.1

To a solution of2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbonitrile(0.500 g, 0.00142 mol) in Tetrahydrofuran (14 mL) was added Lithiumtetrahydroaluminate (0.00569 mol, 1M in THF, 5.7 mL), dropwise at 0° C.The reaction was stirred for 2 hours and quenched with saturated Na₂SO₄until H₂ evolution ceased. MgSO₄ was added and the whole was dilutedwith copious amounts of methylene chloride, filtered over celite, andconcentrated in vacuo. The crude was purified by flash chromatography(1-15% MeOH in DCM spiked with Et₃N) to afford 532 as a yellow solid(238 mg). MS(ESI+) 356.1

Example 533N-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-methanesulfonamide533

To a solution ofC-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine532 (0.050 g, 0.14 mmol) and triethylamine (0.0235 mL, 0.169 mmol) inmethylene chloride (0.902 mL) was added methanesulfonyl chloride (13.1uL, 0.169 mmol) dropwise. The reaction was stirred at room temperaturefor 1 hour. Water was added and the mixture was extracted 3 times withmethylene chloride. The organic layers were combined, dried with MgSO₄,and concentrated. The crude was purified by reverse-phase HPLC to give533 as a white solid (24 mg). MS(ESI+) 434.1. ¹H NMR (400 MHz, DMSO) δ8.31 (d, J=8.2 Hz, 1H), 7.61 (t, J=6.3 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H),7.06 (br, 1H), 5.76 (hept, J=6.1 Hz, 1H), 4.36 (t, J=5.0 Hz, 2H), 4.17(d, J=6.2 Hz, 2H), 3.43 (t, J=4.9 Hz, 2H), 2.89 (s, 3H), 2.32 (s, 3H),1.52 (d, J=6.6 Hz, 6H)

Example 5342-(2-Isopropyl-2H-5-hydroxymethyl[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene534

2-(2-Isopropyl-2H-5-methoxymethyl[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene531 (456 mg, 1.28 mmol) and HBr (8 mL, 48% solution) were heated at 100°C. for 4 h. The reaction mixture was diluted with water and the pHadjusted to ˜pH 8 by the addition of sodium carbonate solution (1M). Themixture was extracted with DCM (5×30 mL) and the combined organicextracts washed with water, then brine, dried (MgSO₄) and concentratedin vacuo. The resultant residue was subjected to flash chromatography(SiO₂ eluting with 0-3% MeOH in DCM) to give the title product (246 mg,56%). A portion of this material was further purified on reverse phasepreparative HPLC (C18 column, gradient 55-98% MeOH in water, 0.1% formicacid) to yield 534. LCMS: R_(T)=4.57 min, [M+H]⁺=343 [ad824015] [73244]¹H NMR 400 MHz (d₆-DMSO) δ: 8.31 (1H, dd, J=7.9, 1.8 Hz), 7.29-7.23 (1H,m), 7.19-7.13 (1H, m), 7.04 (1H, dd, J=7.9, 1.2 Hz), 5.76 (1H, sept,J=6.6 Hz), 5.35 (1H, t, OH J=6.1 Hz), 4.43 (2H, d, J=6.1 Hz), 4.32 (2H,t, J=5.0 Hz), 3.40 (2H, t, J=5.0 Hz), 1.50 (6H, d, J=6.6 Hz)

Examples 535 and 5362-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-3S-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene535 and2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-3R-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene536

To a solution of lithium diisopropylamide (0.0144 mol, 2M inheptane/THF/EtPh, 7.2 mL) in tetrahydrofuran (25 mL) at −78° C. wasadded a solution of 3-Oxo-piperidine-1-carboxylic acid tert-butyl ester(2.00 g, 0.0100 mol) in tetrahydrofuran (5 mL) dropwise. After 15minutes, N-phenylbis(trifluoromethanesulphonimide) (4.303 g, 0.01204mol) in tetrahydrofuran (10 mL) was added. The reaction was slowlywarmed to room temperature and stirred overnight. The reaction wascooled to 0° C. and quenched with saturated NH₄Cl, diluted with water,and extracted 3 times with dichloromethane. The organic layers werecombined, dried with MgSO₄, and concentrated. The mixture was purifiedby flash chromatography (EtOAc/hexanes) to give 0.933 g of5-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester and 1.1234 g of5-Trifluoromethanesulfonyloxy-3,4-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester.

A solution of8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(2.50 g, 0.00617 mol) and potassium acetate (1.816 g, 0.01850 mol) inDimethyl sulfoxide (20.0 mL) was thoroughly purged with N₂. Bispinacolester boronate (1.723 g, 0.006785 mol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.504 g, 0.617 mmol) were added and theflask was sealed and heated to 85° C. overnight. The reaction wasdiluted with dichloromethane and filtered through celite. Water wasadded and the solution was extracted 3 times with dichloromethane. Theorganic phases were combined, dried with MgSO₄ and concentrated. Thecrude was purified by flash chromatography (10-100% EtOAc in hexanes) toobtain2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneas a light yellow solid (1.564 g). MS(ESI+) 453.2

2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.496 g, 0.00110 mol),5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (0.550 g, 0.996 mmol) and sodium carbonate (0.317 g,0.00299 mol) were dissolved in 1,2-dimethoxyethane (5.6 mL) and water(3.1 mL). The reaction was thoroughly degassed with N₂.Tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.0000996 mol) wasadded and the reaction was heated to 80° C. for 3 hours. Water anddichloromethane were added and the mixture was extracted 3 times withdichloromethane. The organic layers were combined, dried with MgSO₄ andconcentrated. The crude was purified by flash chromatography to afford5-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester as a yellow solid (396 mg). MS(ESI+) 508.2

5-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.390 g, 0.768 mmol), was dissolved in Methanol(15 mL). The reaction was run on the H-cube with a Pd/C cartridge andcomplete by LC/MS after the first run. The crude3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylicacid tert-butyl ester (MS(ESI+) 510.3) was dissolved (0.768 mmol) inmethylene chloride (1.0 mL) and trifluoroacetic acid (1.0 mL) andstirred at room temperature for 30 minutes. The solvents were removed invacuo. The crude was purified by reverse-phase HPLC and resolved bychiral SFC to give 14.2+16.8 mg (each enantiomer) 535 and 536 as purewhite solids. MS(ESI+) 410.2.

Example 5372-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-2-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene537

(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)zinc(II) chloride (2.75 mL, 1.02mmol, 0.37M) was added to a 10 mL microwave vial under nitrogen,8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27 from FIG. 4 (200 mg, 0.51 mmol), Pd(OAc)₂ (12 mg) andtri-tert-butylphosphonium tetrafluoroborate (18 mg) were added. Thereaction vessel was sealed and the mixture heated at 100° C. overnight.Aqueous work-up and concentration gave a crude residue which was treatedwith TFA in DCM (1:1 mix). After 1 h at room temperature, the solventwas removed and the residue purified by reverse phase HPLC to give 537(10 mg, 5%). LCMS: 382.1

Example 5384-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H—N-2-methoxyethylpyridin-2-one538

Following the procedures in Example 477, to 505 in DMF was added1-bromo-2-methoxyethane and cesium fluoride to give 538 (0.005 g, 3%).¹H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.13 (s, 1H), 7.74 (d, J=7.2,1H), 7.69 (d, J=8.2, 1H), 7.18 (d, J=8.4, 1H), 6.67 (s, 1H), 6.56 (d,J=7.0, 1H), 5.92-5.75 (m, 1H), 4.44 (s, 2H), 4.08 (t, J=4.8, 2H), 3.61(t, J=4.9, 2H), 3.48 (s, 2H), 3.26 (s, 3H), 1.59 (d, J=6.5, 6H). MS(ESI(+)): m/z 464.2 (M+H)

Example 5394-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H—N-isopropylpyridin-2-one539

Following the procedures in Example 477, to 505 in DMF was added2-iodopropane and cesium fluoride to give 539 (0.011 g, 5%). ¹H NMR (400MHz, DMSO) δ 8.75 (s, 1H), 8.13 (s, 1H), 7.87 (d, J=7.3, 1H), 7.69 (d,J=8.4, 1H), 7.18 (d, J=8.5, 1H), 6.66 (s, 1H), 6.61 (d, J=7.1, 1H),5.93-5.72 (m, 1H), 5.19-4.97 (m, 1H), 4.43 (s, 2H), 3.48 (s, 2H), 1.61(d, J=6.5, 6H), 1.33 (d, J=6.8, 6H). MS (ESI(+)): m/z 448.1 (M+H)

Example 5404-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-(2-isopropoxyl)pyridine540

Following the procedure for Example 478,4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H-pyridin-2-one505 and 2-iodopropane were reacted to give 540. ¹H NMR (400 MHz, DMSO) δ8.81 (s, 1H), 8.24 (d, J=5.4 Hz, 1H), 8.13 (s, 1H), 7.74 (d, J=8.4 Hz,1H), 7.25 (d, J=5.3 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 5.85 (dt, J=13.3,6.7 Hz, 1H), 5.38-5.22 (m, 1H), 4.44 (s, 2H), 3.48 (s, 2H), 1.59 (d,J=6.5 Hz, 6H), 1.32 (d, J=6.0 Hz, 6H). MS (ESI(+)): m/z 448.1 (M+H)

Example 5415-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-1H-pyridin-2-one541

Following the procedures for 128,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulenewas reacted with 6-fluoropyridin-3-ylboronic acid to give2-(2-sopropyl-2H-[1,2,4]triazol-3-yl)-8-(2-fluoropyrid-5-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(1.11 g, 50%). ¹H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.47 (d, J=8.1,1H), 8.38 (t, J=7.8, 1H), 8.12 (s, 1H), 7.61 (d, J=8.4, 1H), 7.49 (s,1H), 7.30 (d, J=8.6, 1H), 5.84 (dd, J=13.2, 6.4, 1H), 4.43 (s, 2H), 3.49(s, 2H), 1.57 (d, J=6.5, 6H). MS (ESI(+)): m/z 408.2 (M+H)

Following the procedures for 330,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(2-fluoropyrid-5-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneand HCl were reacted to give 541 (1.04 g, 100%. ¹H NMR (400 MHz, DMSO) δ11.91 (s, 1H), 8.37 (d, J=8.3, 1H), 8.12 (s, 1H), 7.92 (d, J=9.8, 1H),7.84 (s, 1H), 7.45 (d, J=8.5, 1H), 7.31 (s, 1H), 6.43 (d, J=9.6, 1H),5.85 (dd, J=12.6, 6.2, 1H), 4.40 (s, 2H), 3.46 (s, 2H), 1.56 (d, J=6.5,6H). MS (ESI(+)): m/z 406.1 (M+H)

Example 542{1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethyl}-urea542

A mixture of8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.220 g, 0.000543 mol), tributyl-ethoxyvinyl-tin (0.202 mL, 0.000597mol), and bis(triphenylphosphine)palladium(II) chloride (0.0190 g,0.0271 mmol) was degassed with N₂. The reaction was heated to 100° C.overnight. The crude was hydrolyzed with 10% HCl and extracted 3 timeswith ethyl acetate. The organic layers were combined, dried with MgSO₄and concentrated. The crude was loaded as a solid onto silica andpurified by flash chromatography (45-100% ethyl acetate in hexanes) togive1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethanoneas a white solid (126 mg). MS(ESI+) 369.2

To a solution of1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethanone(0.126 g, 0.000342 mol) in methanol (5.0 mL) was added ammonium acetate(0.140 g, 0.00182 mol) then sodium cyanoborohydride (0.172 g, 0.00274mol). The reaction was stirred at 50° C. overnight. The mixture wasbasified with 1N NaOH and extracted 3 times with methylene chloride. Theorganic phases were combined, dried with Na₂SO₄ and concentrated to give1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethylamine.MS(ESI+) 370.2.

To a solution of1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethylamine(0.120 g, 0.325 mmol) in acetic acid (0.0923 mL) and water (3.45 mL) wasadded a solution of potassium cyanate (0.132 g, 0.00162 mol) in Water(1.0 mL, 0.056 mol) dropwise. The reaction was stirred at 50° C.overnight, cooled down, filtered, and rinsed with cold water. The crudewas precipitated in methanol/water and repurified by reverse-phase HPLCto give 542 as a beige solid (5.5 mg). MS(ESI+) 413.1. ¹H NMR (400 MHz,DMSO) δ 8.27 (d, J=8.2 Hz, 1H), 7.12 (dd, J=8.3, 1.5 Hz, 1H), 6.98 (d,J=1.4 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 5.83-5.68 (m, 1H), 5.47 (s, 2H),4.70 (p, J=7.1 Hz, 1H), 4.44-4.25 (m, 2H), 3.42 (t, J=4.9 Hz, 2H), 2.32(s, 3H), 1.52 (dd, J=6.5, 1.6 Hz, 6H), 1.32 (d, J=7.0 Hz, 3H)

Example 5434-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-1-ethyl-pyridin-2-one543

Following the procedures in Example 477, to 530 in DMF was addediodoethane and cesium fluoride to give 543 (0.734 g, 62%. ¹H NMR (400MHz, DMSO) δ 8.45 (d, J=8.3, 1H), 8.13 (s, 1H), 7.80 (d, J=7.1, 1H),7.58 (dd, J=8.4, 1.9, 1H), 7.43 (d, J=1.8, 1H), 6.72 (s, 1H), 6.66 (dd,J=7.1, 2.0, 1H), 5.84 (dt, J=13.2, 6.5, 1H), 4.42 (s, 2H), 3.94 (d,J=7.1, 2H), 3.48 (s, 2H), 1.56 (d, J=6.6, 6H), 1.24 (t, J=7.1, 3H). MS(ESI(+)): m/z 434.1 (M+H)

Example 5445-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-1-(2-methoxyethyl)-pyridin-2-one544

Following the procedures in Example 477, 541 and 1-bromo-2-methoxyethanewere reacted to give 544 (0.21 g, 23%). ¹H NMR (400 MHz, DMSO) δ 8.39(d, J=8.3, 1H), 8.15 (d, J=2.5, 1H), 8.11 (s, 1H), 7.90 (dd, J=9.5, 2.7,1H), 7.45 (dd, J=8.4, 1.9, 1H), 7.32 (d, J=1.9, 1H), 6.49 (d, J=9.5,1H), 5.84 (dt, J=13.1, 6.5, 1H), 4.41 (t, J=4.9, 2H), 4.16 (t, J=5.4,2H), 3.63 (t, J=5.4, 2H), 3.46 (t, J=4.9, 2H), 3.27 (s, 3H), 1.56 (d,J=6.6, 6H). MS (ESI(+)): m/z 464.2 (M+H)

Example 5452-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-benzenesulfonamide545

To a microwave vial was added benzenesulfonamide (0.0992 g, 0.420 mmol)and potassium acetate (0.124 g, 0.00126 mol) in acetonitrile (2.0 mL)and water (2.0 mL). The mixture was thoroughly purged with N₂.2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.200 g, 0.442 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.0485 g, 0.0420 mmol) were added and the vial was sealed immediately.The reaction was heated to 140° C. for 20 minutes in the microwave.Methylene chloride and saturated NH₄Cl were added and the mixture wasextracted 3 times with methylene chloride. The organic layers werecombined, dried with MgSO₄ and concentrated. The crude was purified byreverse-phase HPLC to give 545 as a white solid. MS(ESI+) 482.1. ¹H NMR(400 MHz, DMSO) δ 8.35 (d, J=8.2 Hz, 1H), 8.05 (dd, J=7.7, 1.3 Hz, 1H),7.67-7.55 (m, 2H), 7.37 (dd, J=7.4, 1.4 Hz, 1H), 7.23 (m, 3H), 7.10 (d,J=1.7 Hz, 1H), 5.79 (hept, J=6.6 Hz, 1H), 4.41 (t, J=4.9 Hz, 2H), 3.46(t, J=4.9 Hz, 2H), 2.33 (s, 3H), 1.54 (d, J=6.6 Hz, 6H)

Example 546(S)-1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-pyrrolidine-2-carboxylicacid amide 546

To a solution of2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-vinyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene(0.200 g, 0.591 mmol) in tetrahydrofuran (20 mL) and water (10 mL) wasadded osmium tetraoxide (0.0473 mmol, 4% wt in water, 0.3 ml) followedby sodium metaperiodate (0.253 g, 0.00118 mol) slowly. The mixture wasstirred at room temperature for 6 hours. The reaction was quenched withsaturated sodium thiosulfate, then diluted with ethyl acetate andextracted 3 times with ethyl acetate. The organic phases were combined,dried with Na₂SO₄ and concentrated to give2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde.MS(ESI+) 341.1

To a solution of2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde(0.100 g, 0.294 mmol) in 1,2-dichloroethane (3.0 mL) was added L-proline(0.0372 g, 0.323 mmol) and 4 Å molecular sieves. After 2 hours, Sodiumtriacetoxyborohydride (0.124 g, 0.588 mmol) was added. The reaction wasstirred at room temperature overnight, diluted with dichloromethane,filtered and concentrated. The crude was redissolved in tetrahydrofuran(1.5 mL). N,N-diisopropylethylamine (0.409 mL, 0.00235 mol), ammoniumchloride (0.0628 g, 0.00118 mol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.128 g, 0.000338 mol) were added and the reactionwas stirred at room temperature for 5 hours. Saturated NaHCO₃ was addedand the mixture was extracted with 3 times with ethyl acetate. Theorganic phases were combined, dried with MgSO₄ and concentrated. Thecrude was purified by reverse-phase HPLC to give 546 as a white solid(15.2 mg). MS(ESI+) 439.2. ¹H NMR (400 MHz, DMSO) δ 8.30 (d, J=8.1 Hz,1H), 8.10 (s, 1H), 7.24 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.2, 1.5 Hz, 1H),7.07 (d, J=1.3 Hz, 1H), 7.04 (d, J=1.7 Hz, 1H), 5.88-5.77 (m, 1H), 4.36(t, J=5.0 Hz, 2H), 3.85 (d, J=13.4 Hz, 1H), 3.43 (t, J=5.1 Hz, 2H), 3.40(d, J=13.5 Hz, 1H), 3.01-2.87 (m, 2H), 2.24 (dd, J=16.3, 8.1 Hz, 1H),2.13-1.99 (m, 1H), 1.77-1.65 (m, 3H), 1.55 (d, J=6.6 Hz, 6H)

Examples 547 and 548(R)-2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-amino-1-oxopropan-2-yloxy)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene547, and(S)-2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-amino-1-oxopropan-2-yloxy)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene548 Step 1:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-hydroxyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

A mixture of8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene27, see FIG. 4 (1.06 g, 2.70 mmol), pulverized potassium hydroxide (303mg, 5.4 mmol), tris(dibenzylideneacetone)di palladium(0) (24.8 mg, 0.027mmol),2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl(26.0 mg, 0.054 mmol) were combined in a sealed tube. The mixture wasthen taken up in 1,4-dioxane (2.4 mL), water (2.4 mL), and sealed. Thereaction mixture was placed in a pre-heated bath and stirred at 100° C.overnight. Added an additional 2.0 eq of pulverized potassium hydroxide,1 mol % tris(dibenzylideneacetone)di palladium(0), 2 mol %2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl,and 0.2 mL of water and 1,4-dioxane and heated at 100° C. for 2 h. Thereaction mixture was filtered through a plug of celite and concentratedin vacuo and the residue purified by flash chromatography (silica, 80 gcolumn, ISCO, 0-100% ethyl acetate in heptane) to afford2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-hydroxyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneas a yellow solid (480 mg, 54%). ¹H NMR (400 MHz, DMSO) δ 9.87 (s, 1H),8.22 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 6.61 (dd, J=8.8, 2.4 Hz, 1H), 6.41(d, J=2.4 Hz, 1H), 5.90 (hept, J=6.6 Hz, 1H), 4.51-4.38 (m, 4H), 1.47(d, J=6.6 Hz, 6H).

Step 2: 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(methylpropionate-2-oxy)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

(81 mg, 0.246 mmol) and dicesium carbonate (240 mg, 0.74 mmol) weresuspended in N, N-dimethylformamide (0.95 mL) and treated with propanoicacid, 2-bromo, methyl ester (55 μL, 0.49 mmol). The resultant reactionmixture was stirred at ambient temperature for 1.5 h, then diluted withwater (25 mL) and extracted into 20% MeOH in DCM (3×25 mL). The combinedorganic phase was dried over sodium sulfate, filtered, and the solventremoved in vacuo to afford racemic2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(methylpropionate-2-oxy)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as acolorless liquid-solid.

Step 3:2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-hydroxy-1-oxopropan-2-yloxy)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(methylpropionate-2-oxy)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (102mg, 0.246 mmol) was dissolved in tetrahydrofuran (0.97 mL) and water(0.97 mL) and treated with as 1.0 M aqueous solution of LiOH (1.23 mL).The mixture was heated at 35° C. overnight. An additional 0.55 mL of the1.0 M aqueous solution of LiOH was added and the mixture continued toheat at 35° C. for 4 h. The resultant solution was partitioned betweenethyl acetate and aqueous 1N HCl, and the layers separated. The aqueousphase was extracted into ethyl acetate, dried over sodium sulfate,filtered, and concentrated in vacuo to afford the racemic carboxylicacid,2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-hydroxy-1-oxopropan-2-yloxy)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene,as a light yellow solid.

Step 4

Ammonium chloride (52.6 mg, 0.98 mmol) and N, N-diisopropylamine (85 mL,0.49 mmol) were added to a solution of the carboxylic acid (98 mg, 0.246mmol) in tetrahydrofuran (0.80 mL). After 5 minN,N,N′,N′-tetratmethyl-O-(7-azabenzotriazol-1-yl)uraniumhexafluorophosphate (103 mg, 0.27 mmol) was added at ambient temperatureand stirred for 2 h. The resultant solution was partitioned betweenethyl acetate and sat. sodium bicarbonate, and the layers separated. Theaqueous phase was extracted into ethyl acetate, dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude residue waspurified via HPLC to afford2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-amino-1-oxopropan-2-yloxy)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azuleneas a racemic mixture of 547 and 548 as a white solid. LC/MS (ESI+): m/z400 (M+H). ¹H NMR (400 MHz, DMSO) δ 8.25 (d, J=8.8 Hz, 1H), 8.08 (s,1H), 7.51 (s, 1H), 7.24 (s, 1H), 6.77 (dd, J=8.9, 2.6 Hz, 1H), 6.60 (d,J=2.5 Hz, 1H), 5.81 (m, 1H), 4.66 (q, J=6.7 Hz, 1H), 4.36 (t, J=4.9 Hz,2H), 3.40 (t, J=4.9 Hz, 2H), 1.54 (d, J=6.6 Hz, 6H), 1.45 (d, J=6.6 Hz,3H). The enantiomers were separated by chiral HPLC and analyzed bySFC/MS.

Instrument: Berger Analytical SFC/MS, Column: ChiralPak AS from ChiralTechnologies, 4.6×100 mm, Sum particle size, Flowrate: 5.0 mL/min,Detection: UV 254 nm, Backpressure setting: 120 Bar, Temperaturesetting: 40 C, Mobile Phase A: CO2, Mobile Phase B: MeOH, Sample was rununder isocratic conditions at 40% mobile phase B, Runtime: 3 minutes,547 Retention Time: 0.70 minutes, 548 retention time 0.48 minutes

Example 601 p110α (alpha) PI3K Binding Assay

Binding Assays: Initial polarization experiments were performed on anAnalyst HT 96-384 (Molecular Devices Corp, Sunnyvale, Calif.). Samplesfor fluorescence polarization affinity measurements were prepared byaddition of 1:3 serial dilutions of p110 alpha PI3K (Upstate CellSignaling Solutions, Charlottesville, Va.) starting at a finalconcentration of 20 ug/mL in polarization buffer (10 mM tris pH 7.5, 50mM NaCl, 4 mM MgCl₂, 0.05% Chaps, and 1 mM DTT) to 10 mM PIP₂(Echelon-Inc., Salt Lake City, Utah) final concentration. After anincubation time of 30 minutes at room temperature, the reactions werestopped by the addition of GRP-1 and PIP3-TAMRA probe (Echelon-Inc.,Salt Lake City, Utah) 100 nM and 5 nM final concentrations respectively.Read with standard cut-off filters for the rhodamine fluorophore(λex=530 nm; λem=590 nm) in 384-well black low volume Proxiplates(PerkinElmer, Wellesley, Mass.) Fluorescence polarization values wereplotted as a function of the protein concentration, and the EC₅₀ valueswere obtained by fitting the data to a 4-parameter equation usingKaleidaGraph software (Synergy software, Reading, Pa.). This experimentalso establishes the appropriate protein concentration to use insubsequent competition experiments with inhibitors.

Inhibitor IC₅₀ values were determined by addition of the 0.04 mg/mL p110alpha PI3K (final concentration) combined with PIP₂ (10 mM finalconcentration) to wells containing 1:3 serial dilutions of theantagonists in a final concentration of 25 mM ATP (Cell SignalingTechnology, Inc., Danvers, Mass.) in the polarization buffer. After anincubation time of 30 minutes at room temperature, the reactions werestopped by the addition of GRP-1 and PIP3-TAMRA probe (Echelon-Inc.,Salt Lake City, Utah) 100 nM and 5 nM final concentrations respectively.Read with standard cut-off filters for the rhodamine fluorophore(λex=530 nm; λem=590 nm) in 384-well black low volume proxi plates(PerkinElmer, Wellesley, Mass.) Fluorescence polarization values wereplotted as a function of the antagonist concentration, and the IC₅₀values were obtained by fitting the data to a 4-parameter equation inAssay Explorer software (MDL, San Ramon, Calif.).

Alternatively, inhibition of PI3K was determined in a radiometric assayusing purified, recombinant enzyme and ATP at a concentration of 1 uM.The Formula I compound was serially diluted in 100% DMSO. The kinasereaction was incubated for 1 hr at room temperature, and the reactionwas terminated by the addition of PBS. IC₅₀ values were subsequentlydetermined using sigmoidal dose-response curve fit (variable slope).

Example 602 In Vitro Cell Proliferation Assay

Efficacy of Formula I compounds were measured by a cell proliferationassay employing the following protocol (Promega Corp. Technical BulletinTB288; Mendoza et al (2002) Cancer Res. 62:5485-5488):

1. An aliquot of 100 μl of cell culture containing about 10⁴ cells (PC3,Detroit562, or MDAMB361.1) in medium was deposited in each well of a384-well, opaque-walled plate.

2. Control wells were prepared containing medium and without cells.

3. The compound was added to the experimental wells and incubated for3-5 days.

4. The plates were equilibrated to room temperature for approximately 30minutes.

5. A volume of CellTiter-Glo Reagent equal to the volume of cell culturemedium present in each well was added.

6. The contents were mixed for 2 minutes on an orbital shaker to inducecell lysis.

7. The plate was incubated at room temperature for 10 minutes tostabilize the luminescence signal.

8. Luminescence was recorded and reported in graphs as RLU=relativeluminescence units.

Alternatively, cells were seeded at optimal density in a 96 well plateand incubated for 4 days in the presence of test compound. Alamar Blue™was subsequently added to the assay medium, and cells were incubated for6 hr before reading at 544 nm excitation, 590 nm emission. EC₅₀ valueswere calculated using a sigmoidal dose response curve fit. The term EC₅₀refers to the half maximal effective concentration and is theconcentration at which a drug induces a response halfway between thebaseline and maximum after some specified exposure time. It is commonlyused as a measure of drug potency.

The anti-proliferative effects of Formula I exemplary compounds weremeasured by the CellTiterGlo® Assay against various tumor cell lines,including the following:

EC50 EC50 EC50 EC50 EC50 Mutation (μmole) (μmole) (μmole) (μmole)(μmole) Cell line Tissue Type Status 127 193 375 440 463 AU565 Breast WT0.037 0.493 0.241 1.235 0.225 BT474 Breast PI3K(amped 0.428 1.634 0.638CAL120 Breast WT CAL51 Breast PI3K/PTEN EFM19-2A Breast WT EVSA-T BreastPTEN 0.147 2.741 0.225 4.932 0.746 HCC1954 Breast PI3K 0.348 1.616 0.340KPL4 Breast PI3K 0.151 0.338 0.103 MCF7 Breast PI3K MDA-MB-231 BreastK-RAS MDA-MB- Breast PI3K 0.060 0.943 1.088 2.606 0.855 361.1 MFM223Breast PI3K 0.739 4.414 0.559 SKBR3 Breast WT 1.728 T47D Breast PI3K0.145 0.569 0.185 Colo205 Colon B-Raf HCT116 Colon PI3K/KRAS KM12 ColonPTEN 1.749 0.321 MDST8 Colon PTEN 1.738 1.721 RKO Colon PI3K LN229Glioma PI3K U87MG Glioma PTEN 0.858 2.093 H1703 Lung(NSCLC) WT H2122Lung(NSCLC) K-RAS 1.174 10 0.542 H520 Lung(NSCLC) PTEN 0.226 0.972537MEL Melanoma PTEN A2058 Melanoma PTEN A375 Melanoma B-Raf IGROV1Ovarian PI3K TOV21GX1 Ovarian PI3K/PTEN PC3 Prostate PTEN 0.145 3.0290.185

Example 603 Caco-2 Permeability

Caco-2 cells are seeded onto Millipore Multiscreen plates at 1×10⁵cells/cm², and cultured for 20 days. Assessment of compound permeabilityis subsequently conducted. The compounds are applied to the apicalsurface (A) of cell monolayers and compound permeation into thebasolateral (B) compartment was measured. This is performed in thereverse direction (B-A) to investigate active transport. A permeabilitycoefficient value, P_(app), for each compound, a measure of the rate ofpermeation of the compound across the membrane, is calculated. Compoundsare grouped into low (P_(app)</=1.0×10⁶ cm/s) or high (P_(app)>/=1.0×10⁶cm/s) absorption potential based on comparison with control compoundswith established human absorption.

For assessment of a compound's ability to undergo active efflux, theratio of basolateral (B) to apical (A) transport compared with A to Bwas determined. Values of B−A/A−B>/=1.0 indicate the occurrence ofactive cellular efflux.

Example 604 Hepatocyte Clearance

Suspensions of cryopreserved human hepatocytes are used. Incubations areperformed at compound concentration of 1 mM or 3 μM at a cell density of0.5×10⁶ viable cells/mL. The final DMSO concentration in the incubationis about 0.25%. Control incubations are also performed in the absence ofcells to reveal any non-enzymatic degradation. Duplicate samples (50 μL)are removed from the incubation mixture at 0, 5, 10, 20, 40 and 60minutes (control sample at 60 minutes only) and added to methanolcontaining internal standard (100 μL)—to terminate the reaction.Tolbutamide, 7-hydroxycoumarin, and testosterone may be used as controlcompounds. Samples are centrifuged and the supernatants at each timepoint pooled for analysis by LC-MSMS. From a plot of ln peak area ratio(parent compound peak area/internal standard peak area) against time,intrinsic clearance (CL_(int)) is calculated as follows: CL_(int)(μl/min/million cells)=V×k, where k is the elimination rate constant,obtained from the gradient of ln concentration plotted against time; Vis a volume term derived from the incubation volume and is expressed asuL 10⁶ cells⁻¹.

Example 605 Cytochrome P450 Inhibition

Formula I compounds may be screened against CYP450 targets (1A2, 2C9,2C19, 2D6, 3A4) at about 10 concentrations in duplicate, with a topconcentration of about 100 uM. Standard inhibitors (furafylline,sulfaphenazole, tranylcypromine, quinidine, ketoconazole) may be used ascontrols. Plates may be read using a BMG LabTechnologies PolarStar influorescence mode.

Example 606 Cytochrome P450 Induction

Freshly isolated human hepatocytes from a single donor may be culturedfor about 48 hr prior to addition of Formula I compound at threeconcentrations and incubated for 72 hr. Probe substrates for CYP3A4 andCYP1A2 are added for 30 minutes and 1 hr before the end of theincubation. At 72 hr, cells and media are removed and the extent ofmetabolism of each probe substrate quantified by LC-MS/MS. Theexperiment is controlled by using inducers of the individual P450sincubated at one concentration in triplicate.

Example 607 Plasma Protein Binding

Solutions of Formula I compound (Sum, 0.5% final DMSO concentration) areprepared in buffer and 10% plasma (v/v in buffer). A 96 well HT dialysisplate is assembled so that each well is divided in two by asemi-permeable cellulose membrane. The buffer solution is added to oneside of the membrane and the plasma solution to the other side;incubations are then conducted at 37° C. over 2 hr in triplicate. Thecells are subsequently emptied, and the solutions for each batch ofcompounds are combined into two groups (plasma-free andplasma-containing) then analyzed by LC-MSMS using two sets ofcalibration standards for plasma-free (6 points) and plasma-containingsolutions (7 points). The fraction unbound value for the compound iscalculated.

Example 608 hERG Channel Blockage

Formula I compounds are evaluated for ability to modulate rubidiumefflux from HEK-294 cells stably expressing hERG potassium channelsusing established flux methodology. Cells are prepared in mediumcontaining RbCl, plated into 96-well plates and grown overnight to formmonolayers. The efflux experiment is initiated by aspirating the mediaand washing each well with 3×100 μL of pre-incubation buffer (containinglow [K⁺]) at room temperature. Following the final aspiration, 50 μL ofworking stock (2×) compound is added to each well and incubated at roomtemperature for 10 minutes. Stimulation buffer 50 μL (containing high[K+]) is then added to each well giving the final test compoundconcentrations. Cell plates are then incubated at room temperature for afurther 10 minutes. Supernatant 80 μL from each well is then transferredto equivalent wells of a 96-well plate and analyzed via atomic emissionspectroscopy. The compound is screened as 10 pt duplicate IC₅₀ curves,n=2, from a top concentration of 100 μM.

Example 609 In Vivo Tumor Xenograft

Animals suitable for transgenic experiments can be obtained fromstandard commercial sources. Groups of Taconic nude mice (were implantedsubcutaneously in the hind flank with MDA-MB-361.1 (PI3K mutant) breastcancer cells. Mouse xenografts were dosed daily for 21 days with drug orvehicle. Tumor sizes were recorded twice weekly over the course of thestudy. Mouse body weights were also recorded twice weekly, and the micewere observed regularly. Tumor volume was measured in two dimensions(length and width) using Ultra Cal-IV calipers (Model 54-10-111; Fred V.Fowler Co., Inc.; Newton, Mass.) and analyzed using Excel v.11.2(Microsoft Corporation; Redmond, Wash.). Tumor inhibition graphs wereplotted using KaleidaGraph, Version 3.6 (Synergy Software; Reading,Pa.). The tumor volume was calculated with formula: Tumor size(mm³)=(longer measurement×shorter measurement)×0.5

Animal body weights were measured using an Adventurera Pro AV812 scale(Ohaus Corporation; Pine Brook, N.J.). Graphs were generated usingKaleidaGraph Version 3.6. Percent weight change was calculated usingformula: Group percent weight change=(1−(initial weight/newweight))×100.

Mice whose tumor volume exceeded 2000 mm³ or whose body weight losswas >20% of their starting weight were promptly euthanized according toregulatory guidance.

The percent tumor growth inhibition (% INH) at the end of study (EOS)was calculated using formula: % INH=100×(EOS mean volume of tumors inanimals given vehicle−EOS mean volume of tumors in animals given thedrug)/EOS mean volume of tumors in animals given vehicle.

Tumor incidence (TI) was determined based on the number of measurabletumors remaining in each group at the end of the study. A partialresponse (PR) was defined as a >50% but <100% reduction in tumor volume,compared with the starting tumor volume, observed on any day of thestudy. A complete response (CR) was defined as a 100% reduction in tumorvolume, compared with the initial tumor volume, observed on any day ofthe study. Data were analyzed and p-values were determined using theDunnett's test with JMP statistical software, version 5.1.2 (SASInstitute; Cary, N.C.). Individual tumor volumes at end of study andmean tumor volume±SEM values were calculated using JMP statisticalsoftware, version 5.1.2. Body weight data were graphed based on the meanpercentage of change from initial body weights±SEM.

Example 610 Phospho AKT Induction Assay

In a 6-well tissue culture plate cells were seeded at 5×10⁵ cells perwell overnight. Cells were treated with an EC₈₀ of the Formula Icompound. Following treatment, cells were washed once with cold PBS andlysed in 1× Cell Extraction Buffer from Biosource (Carlsbad, Calif.)supplemented with protease inhibitors (Roche, Mannheim, Germany), 1 mMPMSF, and Phosphatase Inhibitor Cocktails 1 and 2 from Sigma (St. Louis,Mo.). Determination of protein concentration was performed using thePierce BCA Protein Assay Kit (Rockford, Ill.). Levels of pAkt (Ser⁴⁷³)and total Akt were assessed using bead kits from Biosource (Carlsbad,Calif.) and the Luminex Bio-Plex system (Bio-Rad, Hercules, Calif.).

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, theinvention is not limited to the exact examples shown as described above.Accordingly, all suitable modifications and equivalents may beconsidered to fall within the scope of the invention as defined by theclaims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

We claim:
 1. A method of treating a hyperproliferative diseasecomprising administering a pharmaceutical composition comprised of atherapeutically effective amount of2-(3-amino-1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxamideand a pharmaceutically acceptable carrier, glidant, diluent, orexcipient to a patient having said hyperproliferative disease, whereinthe hyperproliferative disease is cancer selected from breast, colon,glioma, lung, melanoma, ovarian and prostate cancer.
 2. The method ofclaim 1 wherein the pharmaceutical composition is administered to thepatient by injection.
 3. The method of claim 1 wherein the patient isfurther treated with ranibizumab or bevacizumab.
 4. A method ofinhibiting PI3K and/or mTOR in a patient, the method comprisingadministering a therapeutically effective amount of2-(3-amino-1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxamidetogether with a pharmaceutically acceptable carrier, glidant, diluent,or excipient to the patient.
 5. A process for making2-(3-amino-1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxamidecomprising reacting2-[5-amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylicacid and methylamine hydrochloride.